The diabetes epidemic continues to grow at alarming rates. In New York City, for example, where there is an expanding population of ethnic minorities who are susceptible to acquire Type 2 diabetes, the prevalence of diagnosed diabetes in the borough of the Bronx is already estimated to be 18 (http://www.nyc.gov/html/doh/downloads/pdf/email/dohmhnews5-04.pdf). Most frighteningly, the disease is afflicting a younger population and causing premature disability and death.(1) As a result, the New York City Board of Health recently mandated electronic reporting of Hemoglobin A1c (HbA1C) values in order to track glycemic control, map the epidemiology and identify populations with poor metabolic control.

Hemoglobin A1c (also known as glycohemoglobin, glycated hemoglobin and glycosylated hemoglobin A1C) is used as a disease barometer because it correlates well with outcomes.(2),(3),(4),(5),(6),(7) As a result of data from the Diabetes Control and Complications Trial (DCCT), HbA1c has become the gold standard to assess glycemic control. While the A1C reflects mean blood glucose over the entire 120-day life span of the red blood cell, it correlates best with mean blood glucose over the previous 8 to 12 weeks. The American Diabetes Association recommends obtaining HbA1c at least twice a year in patients under good control and quarterly in patients whose treatment has changed or whose goals are not being met.(8) Though glycemic targets should be individualized for each patient -- balancing life expectancy and existing complications against the risk of hypoglycemia -- the recommended target value for HbA1c is less than 7% or as close to normal (less than 6%) without causing significant hypoglycemia. This goal, however, remains unmet with only 37% of adults having values below 7% nationwide.(9)

Type 1 diabetes mellitus (T1DM) and Type 2 (T2DM) are completely different disorders that share common complications related to large and small vessel disease. The main defect in Type 2 diabetes is insulin resistance characterized by hyperinsulinemia early in the disease. In contrast, insulinopenia is a distinctive finding in Type 1 diabetes. Though treatment varies greatly, the majority of individuals with T2DM can be managed over the long-term with healthy lifestyle changes and/or oral antidiabetic agents, while patients with T1DM always need insulin replacement therapy. It should be noted, however, that when insulin is used in Type 2 diabetes, high doses are needed to overcome the insulin resistant state.(10),(11)

Adequate physiological replacement of insulin remains labor intensive and far from perfect as shown by the DCCT study(2) with hypoglycemia as the main limiting factor (Figure 1).

In the following case report, we describe the diagnosis of and initial management of a new patient with Type 1 diabetes.

Case Report A 51-year-old white male dentist developed "poly-symptoms" including polyuria, polydipsia, polyphagia, and a 20-lb weight loss over two months. He was previously in excellent health, played racquetball at least three times a week and followed healthy eating habits with a diet rich in fruits and vegetables. Elevated cholesterol was treated with atorvastatin 10 mg daily for one year. He had no other meaningful past medical history. His father had coronary heart disease manifested at age 50 and expired at 78 without diabetes. His mother has diabetes with chronic complications and his younger sister and an older brother also have diabetes. The physical examination revealed a healthy muscular male, 6 feet tall, weighing 172 lb with a BMI of 17 kg/m2. His blood pressure was 128/78 mm Hg and his pulse 60 per minute. There was no evidence of any chronic diabetic complications. The neurological examination including a 10 g monofilament test was normal. He did not have anatomic abnormalities in his feet and or evidence of peripheral vascular disease. A dilated eye examination obtained at a subsequent visit was normal. A random blood sugar done in the office was 246 mg/dl.

The presentation of either Type 1 or Type 2 diabetes is not always apparent by a history and physical examination. In this case report, the patient had a history suggestive of Type 2 diabetes based on his age, strong family history and insidious onset. However, his phenotype (thin, Caucasian, low triglycerides, high HDL-cholesterol) was most consistent with Type 1 diabetes. Further laboratory tests are required to establish the correct diagnosis.

Definition and Classification

Diabetes mellitus is a heterogeneous and multifactorial group of metabolic diseases characterized by hyperglycemia secondary to defects in insulin secretion, insulin action or both. The classification of the disease is now based on its pathophysiology rather than pharmacological treatment, making it more uniform and reflecting the current knowledge of the disease.(13) Chronic hyperglycemia is associated with pathognomonic changes and failure of various organs, especially the eyes, kidneys and nerves. Individuals with hyperglycemia are also subject to the accelerated cardiovascular disease that causes premature morbidity and mortality.

Pathogenic processes involved in the development of diabetes range from autoimmune destruction of the insulin producing-cells in the Islets of Langerhans of the pancreas, with consequent insulin deficiency,(12) to abnormalities in insulin signaling that result in resistance to insulin action. The vast majority of cases of diabetes fall into two broad etiopathogenetic groups. In one group (T1DM), the cause is an absolute deficiency of insulin secretion. Individuals at increased risk of developing this type of diabetes can often be identified by serological evidence of an autoimmune process of the pancreatic islets and by genetic markers. In the second and more prevalent group (T2DM), the cause is a combination of resistance to insulin action with inadequate compensatory insulin secretory response.

Making the Diagnosis

The diagnosis of either Type 1 or Type 2 diabetes can often be established by the medical history and phenotypic presentation. In this Cyberounds^®, we are focusing on the diagnosis of T1DM. The parameters shown in Table 1 are helpful to establish the diagnosis.

Type 1 diabetes mellitus accounts for about 5 percent of all cases and results from autoimmune destruction of the insulin-producing β-cells in the Islets of Langerhans, usually leading to absolute insulin deficiency.(12) This process occurs in genetically susceptible subjects and it is probably triggered by one or more environmental factors such as pregnancy-related and perinatal influences, viruses and ingestion of cows' milk and cereals. The genetic susceptibility is based in polymorphisms of five genes known to influence the risk of T1DM:

1. HLA-Dqalpha
2. HLA-Dqbeta
3. DLA-DR
4. Preproinsulin
5. PTPN22 gene

Genes in both the major histocompatibility complex (MHC) and elsewhere in the genome influence risk but only HLA alleles have a large effect.

The pancreatic β-cells suffer a progressive and relentless attack that terminates in failure to produce insulin. The rate of β-cell destruction can be rapid, particularly in infants and children, but may be more insidious in adults.(14) At a later stage of the disease, there is little or no insulin secretion that can be assessed by low levels of plasma C-peptide determinations.

The typical patient with newly diagnosed T1DM is young, Caucasian and can present in diabetic ketoacidosis. Family history of Type 1 diabetes is found in only 10% of patients; identical twins have a 35-50% concordance. Patients with T1DM have a lower body mass index and less endogenous insulin secretion (as measured by stimulated serum C-peptide concentrations).(14),(15) Some Type 1 diabetes (previously known as "juvenile diabetes" or "insulin dependent diabetes") can, however, masquerade as Type 2 diabetes (previously known as "adult onset diabetes" or "non-insulin dependent diabetes"). This version arrives late in life, even in the 8th and 9th decades, with an insidious onset, and is one of the reasons why the classification of diabetes was changed according to the pathogenesis rather than age of presentation or type of treatment.(13),(17)

Finally, there are some atypical presentations of Type 2 diabetes that can resemble Type 1. Common among the Caribbean Black population, for example, are patients with severe pancreatic β-cell dysfunction often presenting with significant hyperglycemia or ketoacidosis resembling Type 1 diabetes. Obesity is usually present in this population and islet cell antibodies are negative. These patients usually recover their insulin secretion capacity and, therefore, do not require insulin replacement therapy.(20),(21),(22)

Autoimmune Destruction

Markers of autoimmune destruction of the β-cells include islet cell autoantibodies (ICAs), autoantibodies to insulin (IAAs), autoantibodies to glutamic acid decarboxylase (GAD₆₅) and autoantibodies to the tyrosine phosphatases.(15) At least one or more of these autoantibodies is present in 85-90% of patients.(16) The presence of either anti-ICA or anti-GAD antibodies identifies patients that, while thought to have type 2 diabetes, will respond poorly to oral antidiabetic drug therapy, are at increased risk for developing ketoacidosis and should be treated early with insulin replacement. Some patients with T1DM have no evidence of autoimmunity and have no other known cause for beta-cell destruction and are classified as idiopathic diabetes mellitus.(19)

Some individuals may retain residual β-cell function for sufficient time to prevent ketoacidosis but eventually will need insulin therapy. The adult form of this type of diabetes can account for up to >30% of all cases in certain populations in Northern Europe. The defect of insulin secretion can be prolonged due to slower β-cell destruction. This type of diabetes is known as Latent Autoimmune Diabetes of the Adult (LADA).(18) The diagnosis is often overlooked, thus patients are improperly treated as T2DM during the early stages. Because of the autoimmune nature of T1DM, patients are at increased risk for developing other disorders such as autoimmune thyroid disease and rheumatoid arthritis.

Regardless of presentation, patients with Type 1 diabetes have an absolute requirement for insulin therapy and will develop diabetic ketoacidosis if not given insulin.

Case Report (Continued) Our 51-year-old dentist's presentation was not typical of either Type 1 or Type 2 diabetes. While age, slow development of hyperglycemia and strong family history suggest Type 2 diabetes, his phenotype (thin, Caucasian, low triglycerides, high HDL-cholesterol) and catabolic state are more consistent with Type 1 diabetes. The presence of anti-ICA and or anti-GAD antibodies and a low C-peptide will help establish the correct diagnosis of Latent Autoimmune Diabetes of the Adult (LADA). Prior to obtaining further laboratory studies, based on the above presentation and an elevated blood sugar, the diagnosis of diabetes was established. During this initial visit, late on a Friday afternoon, the patient was given a glucose monitor, without proper instruction, and was given a Novolog mix 70/30TM pen syringe (recombinant DNA human insulin with 70% protamin aspart suspension and 30% soluble aspart insulin) sample (Tables 2 and 3).

Case Report (Continued) The patient was told to inject 20 units before breakfast and 10 units before dinner. He had problems monitoring his capillary blood sugars over the weekend but was able to call the toll-free number printed on the back of his monitor and received the proper advice on its use. Ten days after treatment was started, he experienced two episodes of hypoglycemia with values in the 40s and 50s. The patient had not been instructed how to recognize or treat hypoglycemia and was unaware of what was happening. He, therefore, decided to change physicians, as he was dissatisfied with the hasty initial encounter and poor follow-up by the endocrinologist.

The patient presented in a catabolic state for which the most effective treatment is insulin therapy. Furthermore, as the diagnosis of Type 1 diabetes was not ruled out, it is safer, when in doubt, to treat with insulin, as failure to treat with insulin could precipitate a hospital admission or development of ketoacidosis. Oral antidiabetic agents may or may not work.

Unlike many patients with recent onset diabetes whose blood sugars are exacerbated by drinking excessive amounts of sugar-containing beverages in response to their increased thirst, this patient followed a healthy diet and exercise regimen -- modifications in lifestyle were not necessary and would not be associated with significant improvement.

A patient with new onset diabetes needs to spend a significant time learning the so-called essential or "survival skills" (self-monitoring of blood glucose, recognition and treatment of hypoglycemia, self-injecting of insulin). In addition, contact information for questions and/or emergencies need to be provided. Appropriate management of this first-time, newly diagnosed Type 1 patient should have included more patient education (see below).

Let's also look at why the other answers were incorrect because this was an important moment in the patient's treatment:

The patient was in a catabolic state. He was not obese and/or insulin resistant. To restore an anabolic state and treat "glucose toxicity." insulin treatment works better than metformin which enhances insulin-mediated inhibition of hepatic glucose production and stimulates of glucose transport into muscle. Metformin treatment was, therefore, not indicated.

While laboratory tests would have been useful, he needed to be treated with insulin in view of the clinical manifestations. The diagnosis of Type 1 diabetes was not ruled out and, when in doubt, it is better to treat with insulin in order to avoid a possible hospital admission or development of ketoacidosis.

"Treatment with insulin is not indicated" is incorrect because insulin is the most effective treatment for a patient presenting in a catabolic state.

Exenatide is used as adjunctive therapy for patients with Type 2 diabetes who are inadequately controlled on oral agents; it has not been approved as first line therapy but more importantly it has no role and is contraindicated in Type 1 diabetes (www.byetta.com/index.jsp).

Elevated blood sugars associated with the typical "poly" symptoms of diabetes (polyuria, polydipsia, polyphagia and weight loss) describe a metabolic derangement that can cause "glucose toxicity." This term was coined to identify a condition where hyperglycemia begets more hyperglycemia by increasing peripheral insulin resistance and decreasing β-cell insulin production.(23),(24) Once euglycemia is restored, these patients become more insulin sensitive.(25) When the insulin regimen is left unchanged, hypoglycemia may develop as the patient becomes more insulin sensitive. It is important to explain this concept to patients, particularly in early onset diabetes, to avoid severe hypoglycemia or hospitalizations.

An incorrect insulin dose would have resulted in the development of hypoglycemia immediately rather than one week later. Decreased β-cell function is a component of the disease in Type 1 and Type 2 diabetes but doesn't cause hypoglycemia. Glycogenolysis, the conversion of glycogen into glucose, causes increased hepatic glucose production and hyperglycemia but not hypoglycemia. If Novolog 70/30^® insulin was the cause of hypoglycemia it would have developed upon initiation of treatment.(26) We will discuss insulin therapy in detail in our next Cyberounds: New Frontiers in the Management of Type 1 Diabetes Mellitus.

Essential Education for Diabetes Self-Management

Patients who are prescribed insulin for the first time need to be taught, without delay, essential self-care skills, also known as "survival skills" that include insulin self injection, self blood glucose monitoring, and recognition and treatment of hypoglycemia. Self-demonstration of these skills and providing instructional material that matches what was taught go a long way in promoting adherence; these educational materials can often be obtained from pharmaceutical companies. In view of the fears and potential emergent circumstances in a newly diagnosed patient, provider contact information must be given.

Insulin Administration

We will discuss insulin therapy in our subsequent Cyberounds^®: New Frontiers in the Management of Type 1 Diabetes Mellitus.

Hypoglycemia

Symptoms of hypoglycemia such as palpitations, diaphoresis and nervousness are manifestations of excess counterregulatory hormones such as catecholamines. Documentation is important, as some patients feel "low" but do not have true hypoglycemia, while others have hypoglycemia unawareness with asymptomatic low blood sugars. When hypoglycemia occurs, rapid provision of glucose is necessary. The "15 rule" is used to teach patients that consuming 15 grams of pure carbohydrate raises blood sugar in about 15 minutes. Treating hypoglycemia with more than this amount or with a high fat food like a candy bar not only raises blood sugar excessively but also delays the blood sugar rise due to the prolonged gastric emptying.

Medical-Nutrition Therapy

There is no such a thing as an "ADA" diet. Instead medical nutrition therapy consists of a heart-healthy diet that is tailored to each patient's individual needs. In-depth diet education is lengthy and not realistic during the first visit. Consistency in both timing of meals and amounts of food is useful initially before further education is given; flexibility will increase once carbohydrate counting is learned. When fixed combination insulin regimens are prescribed, eating three meals at regular times in concert with the insulin peaks must be emphasized. Delaying or skipping meals may result in hypoglycemia. Patients who drink excessive amounts of sugar-containing beverages (sodas and juices) are encouraged to stop this habit.

Case Report (Continued) It is important to give the lab results. Upon consultation with a second endocrinologist one week later, a random capillary blood glucose (CBG) of 56 mg/dl was treated in the office with glucse tablets. A history and physical examination were again obtained and laboratory tests were ordered. The patient was told that laboratory tests may be helpful in determining if he had Type 1 or Type 2 diabetes. Management was discussed among team members and it was decided to change the patient's insulin regimen from Novolog® 30 to Lantus® glargine 12 units daily. The most essential skills of diabetes self-management (glucose monitoring, identification and treatment of hypoglycemia, and insulin administration) were taught to the patient until he was able to demonstrate his ability to do it correctly. One week later the following laboratory results were reviewed by phone with the patient: HbA1c of 11%, random glucose of 121 mg/dl with a C-peptide of 0.7 ng/m; high titers of glutamic acid dehydrogenase (anti-GAD) antibodies of 49.5 U/ml. His lipid profile on atorvastatin 10 mg daily included a total cholesterol of 146 mg/dl, LDL-cholesterol of 60 mg/dl, HDL-cholesterol of 74 mg/dl and triglycerides of 74 mg/dl. The rest of the laboratory tests, including a microalbumin/creatinine ratio, were normal. The patient was asked to reschedule an appointment for further intensification of his regimen.

Intensive insulin therapy should be attempted in all patients with Type 1 diabetes as early as possible in the course of disease.(10),(11) Both patient and physician education/support are required to perform this task safely. Additional data from the DCCT reinforce the importance of beginning intensive therapy immediately after the diagnosis of Type 1 diabetes is made in order to prevent small vessel disease microvasculopathy (retinopathy, nephropathy)(3),(4),(5) and large vessel disease (cardiovascular disease).(2),(9) Patients with early Type 1 diabetes and residual beta-cell function (as evidenced by a serum C-peptide) receiving intensive therapy are less likely to lose residual beta-cell function and will have less variability of glucose-related changes short-term and long-term.(27)

Summary

While the diagnosis of Type 1 versus Type 2 diabetes can often be straightforward, it can, at times, be difficult to establish. In this case report, the patient had an unusual presentation of Type 1 diabetes known as Latent Autoimmune Diabetes in Adults (LADA). While his history suggested Type 2 diabetes, his phenotypic presentation (thin, low triglycerides and high HDL indicative of insulin sensitivity) suggested Type 1 diabetes. In such a patient, laboratory evaluation is necessary to establish the diagnosis.

LADA patients need insulin replacement therapy. Patients started on insulin require ample time to learn the essential skills needed for safe adherence to their regimen before they are sent home. In-depth training can take place at a later time. It is important to approach education and counseling utilizing a diabetes team when available and to provide patients with newly-diagnosed diabetes with contact information for possible questions about management of their disease.

Our next Cyberounds^® Endocrinology: New Frontiers in the Management of TIDM will explore the new insulins and new insulin delivery systems.