Friday the 13Th Scribes: Kellie & Patti

Friday the 13th Scribes: Kellie & Patti ICM – 8:00AM Dr. MacAdams

Type 1 Diabetes

1st Case Presentation:  A 26 year old female with a 3 year history of diabetes, previously treated with oral agent therapy as though she was a type 2 diabetic presents to the hospital. Her blood sugar control had been pretty poor, but she had been more or less asymptomatic.  More recently, however, she began to lose weight and was complaining of fatigue, thirst, and nocturia. At that point she was referred to the endocrine clinic, and her examination was pretty much unremarkable.  Her glycohemoglobin was 12.7 (normal is <6.4%). Her random blood sugar was 346 mg%, with a total CO2 of 14.  Urinalysis showed large ketonuria but no evidence of proteinuria, and serum acetone was positive at a 1:4 dilution.  The patient was placed on insulin therapy, and oral agent therapy was discontinued. Her insulin regimen consisted of 12 units of NPH in the morning and 4 units of NPH in the evening, which is a pretty small dose. Her blood sugar dropped down to an average preprandial glucose of 164, and she gained about 9 pounds over the next 6 weeks.  Her symptoms improved dramatically, and her glycohemoglobin declined to 7.4%.  The issues touched on by this case include the pathogenesis of type 1 diabetes, the entity of preketotic type 1 diabetes, the etiology of the major symptoms of diabetes, the uses of glycohemoglobin measurements, and the objectives in treatment of these patients. Pathogenesis of Type 1 Diabetes  Type 1 diabetes is a disease of insulin deficiency, while type 2 is a disease of insulin resistance. They share in common the fact that they both produce hyperglycemia, but conceptually you want to separate these two disorders.  Most of the patients with type 1 diabetes could be classified as having type 1A diabetes, an autoimmune form of this disorder. A few could be classified as being type 1B (nonautoimmune), which would include patients following pancreatectomies. Type 1 is a gradual and progressive destruction of endogenous insulin secretion.  The overall prevalence of type 1 diabetes in the United States is about 0.4%. The risk is about 6 % in first degree relatives. Identical twins have a 33% concordance rate; this implies that genetics are important, but there are environmental factors that trigger the immune process that leads to type 1 diabetes and those are equally or slightly more important than the genetic background.  Over the past 5 years or so, the actual genetic basis for this disease has begun to surface.  42% of inheritable risk is carried in the HLA portion of chromosome 6. Over 90% of the type 1 diabetics have one of the following two genotypes: DR3,DQB*0201 or DR4,DQB*0302. He showed a graph of the incidence of type 1 diabetes in a population vs. the prevalence of the specific genotypes above – it was essentially a linear relationship.  The specific genotypes described above result in the replacement of an asparagine at position 57 of the beta chain of the MHC on monocytes. It is a single amino acid defect. The groove between the alpha and beta chains has a configuration dependent on the amino acid sequence of the chains; the conformational change induced by this single amino acid substitution alters the recognition of the antigen (who's identity is still being sought). This allows the monocyte to activate the T-cell, which then goes on to cause beta cell destruction. “It is not quite as simple as I am making it sound.”  There are other inheritable tendencies (HLA types) which increase or decrease the likelihood of developing type 1 diabetes. This is a polygenic disorder, but we have good evidence that one single amino acid substitution is responsible for most of the cases of type 1 diabetes.  Clearly, environmental factors are very important as well. However, these factors are difficult to identify because the patient does not become symptomatic until most of the beta cells have been destroyed. This is the main reason why we have not progressed a whole lot in the understanding of environmental causes of type 1 diabetes.  Viral infections may be involved.

1  It was first believed that the virus directly attacked the beta cells, but this is probably not the case. Autopsies have been performed on numerous patients who were recently diagnosed with type 1 diabetes, and beta cell infection by viral particles was seen in only 4 cases worldwide.  It is much more likely that the viral attack triggers an immunological response, which then in turn leads to the beta cell destruction. An interesting fact is that an important enzyme in islet cell physiology, GAD (glutamic acid decarboxylase), has sequence homology with a Coxsackie B viral protein coat. It may be that antibodies directed at the protein coat can crossreact with GAD in the beta cells and trigger the autoimmune response.  He did not go over the slide about the role of cow’s milk and high levels of nitrates in the drinking water.  Islet Cell Antibodies  He showed an immunohistological assay where beta cells are placed on a slide and serum from the patient is added. Then look for evidence of fixation of immunoglobulins in the patient’s serum to the beta cells. This assay has the advantage of being able to screen for an infinite number of unknown antibodies that may be attacking the beta cells, but it has the disadvantages of not knowing which antibodies those are and being difficult to standardize or replicate.  In the past 5-10 years we have started using radioimmunoassays (RIAs) directed at antibodies against specific beta cell proteins. The down-side of this is that there may be proteins that we don't know about that are important in the pathogenesis of type 1 diabetes, and we don’t have an RIA for them so we aren't detecting them. The up-side is that it is a very simple test to perform.  The anti-GAD antibody has become the most frequently employed assay to detect autoimmune activity, but this Ab is found in only 70% of newly diagnosed type 1 diabetics.  More recently anti -IA2 ( anti-insulinoma-associated peptide 2) has been developed. It is encountered in slightly fewer patients than anti-GAD, but it has the advantage of correlating better with the cellular immune system attack on the beta cells. While anti-GAD tells you that at some time in the past the patient had these antibodies, the anti-AI2 titer reflects the ongoing islet cell destruction, so it is probably of more use. Preketotic Type 1 Diabetes  Type 1 diabetes is a very progressive disorder; it takes many years from the initial attack to the clinical recognition. It takes a 60% beta cell loss before the insulin levels begin to decline and the blood sugar begins to rise.  The postprandial blood sugar rises first; this reflects a reduction in the ability of muscle to clear circulating glucose, and we would detect this with a glucose tolerance test.  With further loss of insulin secretion, we see increasing gluconeogenesis. This raises the fasting blood sugar, so the patient will have both postprandial and fasting hyperglycemia. At this point, one really couldn't distinguish between a type 1 and a type 2 diabetic – they look the same. During this phase we can administer an insulin secretagogue like a sulfonylurea to stimulate some insulin secretion; this will work for a while, but eventually hyperglycemia will become a problem once again, and insulin therapy will be required.  Eventually the insulin levels get so low that fat tissue lipolysis becomes unrestrained. Fat tissue is much more sensitive than muscle and liver to the effects of insulin, so the insulin levels will have to fall to about one tenth of that required to cause hyperglycemia before we will see enhanced lipolysis. Lipolysis leads to the liberation of glycerol, which is turned into glucose; this raises the blood sugar even more, but more importantly the excess fatty acids are converted into ketone bodies. At this point the patient is no longer a preketotic type 1 diabetic, but a ketosis-prone diabetic. Ketosis Prone Type 1 Diabetes  In this phase, the insulin level has gotten critically low, and fat is being broken down at an accelerated rate. The body is beginning to produce ketones, especially acetoacetate. The kidney readily eliminates ketones from the bloodstream, so there are no clinical manifestations and the patient is asymptomatic, but if you checked the urine you would find that it was loaded with ketones. Eventually, however, the process accelerates to the point that the kidney can no longer eliminate the ketoacids, so they accumulate and cause ketosis.  The patient discussed in the case above is not clinically ketoacidotic, but she is clearly biochemically ketotic, so insulin therapy is mandatory at this point. In any patient with known type 1 diabetes, the

2 finding of ketonuria must always be regarded as the initial finding of ketoacidosis. These patients must be treated very aggressively or they will rapidly deteriorate and end up in the ICU.  The typical symptoms of advanced ketoacidosis are nausea, vomiting, and dypsnea, but early on the symptoms may be very mild and nonspecific. It is important to teach the patient how to detect the early stage; this is done by having them check their urine for ketones at home with ketostix (a urine dipstick) every time that their blood sugar has gotten out of control or they feel ill, especially if they are nauseated. These patients need to be told that nausea is the cardinal manifestation of ketoacidosis, and before they assume it is anything else they need to check their urine for ketones and make sure they are not developing keotacidosis.  He did not discuss the slide titles “Honeymoon period” of type 1 diabetes. Causes of Principal Symptoms of Diabetes  Most of the symptoms of diabetes are related to the high blood sugar. Hyperglycemia results from an increase in hepatic gluconeogenesis; pyruvate and alanine liberated by muscle breakdown are turned into glucose (the muscles are digested and turned into sugar). The result is muscle wasting and weakness.  Once the blood sugar rises above the renal threshold (usually 180 mg%), the patient will lose glucose in the urine at a fairly marked rate, and can lose 500+ calories a day. Consequently, these patients are losing a lot of weight. The glucose pulls water with it, so patients will complain of dehydration, excess thirst, and polyuria. Purpose of Treating Hyperglycemia  The symptoms of type 1 diabetes can be controlled by getting the blood sugar below 200 mg%. At that juncture, the patients won’t have thirst or nocturia, and they are not in such a catabolic state that they are weak and tired. However, blood glucose around 200 is unacceptable control; this will not prevent the long term complications of diabetes, which include the microvascular complications (retinopathy and nephropathy) and the macrovascular complications (ischemic heart disease that may lead to MI, peripheral vascular disease that may lead to CVA, and peripheral vascular occlusive disease that may lead to amputations).  We now have compelling evidence that strict control of blood sugar can reduce the appearance and progression of the microvascular disease and its complications.  Macrovascular complications, on the other hand, turn out to be more complicated; it is not clear what the glucose relationship is to the development of macrovascular complications. There is some indication that a level of glucose control that exceeds that which we routinely employ for the prevention of microvascular complications will be necessary. We also need to address the other factors that contribute to macrovascular disease in these patients: hyperlipidemia, cigarette smoking, and hypertension in particular. Uses of Glycohemoglobin Measurements  Glycohemoglobin is called a number of things: glycosylated hemoglobin, glycated hemoglobin, GHb, HbA1c.  It is one of many glycosylated end products that are formed by the reaction of a free nitrogen on an amino acid and a hydroxyl group on glucose.  We use it to determine how well we are controlling the disease.  Hemoglobin remains in the circulation throughout the entire lifetime of the RBC (about 4 months). The glycosylation process is very slow, and it occurs at a rate which is directly dependent on the ambient glucose. This process is never completed; on average about 5% of the available hemoglobin becomes glycosylated in the normal individual. So by measuring how much glycohemoglobin a patient has, we can infer what the average blood sugar during the previous 2 months ( half life of RBC) must have been.  Next he showed a graph of data from the DCCT, which was a large multicenter study looking at type 1 diabetics to compare the level of glucose control with the progression of complications. It was this study that definitively determined that controlling blood glucose helps to prevent complications.  What level of glucose control is required to protect against macrovascular disease? The DCCT had patients checking their glucose levels 6-8 times a day at home and taking the average of all those readings over one year; then the clinicians measured the same patients glycohemoglobin 4 times throughout the year and tried to correlate the mean blood sugar with the mean glycohemoglobin. They found that a beautiful linear relationship occurred.  The following formula allows you to estimate the average glucose level over the last two months using the glycohemoglobin result. Formula: take the glycohemoglobin of the patient and subtract the upper

3 limit of normal for the assay that you are employing. Then multiply that by 40 and add the result to 100.  This group of patients had an average glycohemoglobin result of 6.1, and if we look at their measured/recorded blood glucose levels, we would see that they range from nearly 200 to well below 100. However, if we used the formula above to estimate their average glucose, we would assume that they all had a blood sugar averaging around 120. In reality, there is a tremendous amount of variation.  In addition, patients who had an average blood sugar of 100 had glycohemoglobins that ranged from less to 5 to nearly 8. In other words you, can't take the glycohemoglobin too literally; it is a useful tool, but there are limitations imposed by this kind of scatter.  One thing you can do is look at the change in the glycohemoglobin from visit to visit because that tends to be extremely reproducible, but the absolute value is much more individually variable. For this reason, you cannot use glycohemoglobin values to diagnose diabetes, but you can use them to follow a diabetic patient.  The DCCT clearly showed the relationship between glycohemoglobin and the appearance or progression of microvascular complications. He showed a graph that plotted the rate of progression of diabetic retinopathy vs. the glycohemoglobin value. It was an exponential relationship; after you get to a certain HbA1c value, the rate at which the progression of retinopathy occurs accelerates. If you can keep the glycohemoglobin below 7, your patient has a chance of about 2 in 100 of progression of their retinopathy over the next year, which is pretty good odds. (The ADA recommended target is 7 for glycosylated hemoglobin.) If you can get it a little bit lower, you can further reduce the progression of retinopathy, but you are more likely to induce hypoglycemia. Screening for and Targets to Reach to Avoid the Complications of Diabetes  These patients need annual opthamological evaluations.  They need to annual urine albumin measurements to look for early diabetic nephropathy, a microvascular complication very similar to retinopathy.  We need to ensure that they have adequate blood pressure control. The recommendation is that mean arterial pressure be maintained at less than 100. Formula: MAP= (systolic/3 + 2*diastolic/3).  Routine foot examinations  Quarterly glycohemoglobin determinations – the target is to achieve 1% above the upper limit of normal  Annual lipid profile  The target is to keep the LDL <100. In the general population, it is recommended that the LDL<160, but diabetics are very susceptible to microvascular disease, so the American Diabetes Association wants it <100. We use HMG inhibitors and can achieve this fairly easily.  HDL cholesterol >35  Triglycerides <180  Regular home glucose monitoring – targets are preprandial glucose around 120 and postprandial <180. Case Presentation 2  A 17 year old male, type 1 diabetic for 5 years with no complications presents to the ER.  His insulin regimen consists of the following: he takes 42 units of NPH and 6 units of humalog in the morning, 4 units of humalog at lunch, 6 units of humalog at supper, and 20 units of NPH at bedtime.  In preparation for a tonsillectomy, his ENT physician recommended that he delete his morning dosage because he was not going to be eating.. Makes sense right? But upon returning home that evening after the procedure, he noticed that his blood sugar was 380 mg% and per the instruction he had been given he took his pre-supper shot of 6 units of humalog. By bedtime, he was vomiting. His family contacted the ENT physician who said it was probably an anesthetic reaction and not to worry about it. The patient took his usual night time dose of 20 NPH, and by the next morning was vomiting uncontrollably and was taken to the ER. He was in severe DKA, his total CO2 was down to 4, his serum acetone was positive at a dilution of 1:16, and his potassium was 6.5. This patient in the old days would have died. He was admitted to ICU, and 2 days later was dismissed on the same insulin regimen he had been taking before he had his tonsillectomy.  The points brought out by this case:  First, it is necessary that type 1 diabetics take their insulin – ALWAYS! Insulin is to the type 1 diabetic as oxygen is to humans.

4  Diabetics also need to be able to identify early ketoacidosis at home. Typical Insulin Regimen Used for Type 1 Diabetics  Long-Acting Insulins  Ultralente – soon to be eclipsed by a new preparation called Glargine. It should be available in the next few weeks. Ultralente had a bad reputation because it is very inconsistently absorbed, so it was hard to create a consistent baseline insulin level.  Glargine – it should be better absorbed, and will be a major advantage in treating type 1 diabetics.  Intermediate-Acting Insulins  Lente and NPH – these are very similar, not exactly interchangeable, but very similar.  Short-Acting Insulins  Regular – this one is the original insulin. The onset of action is about 30 min, and it peaks around 2 hours. It lasts about 6 hours.  Lispro (Humalog) – the rearranged regular insulin molecule made to get into the system faster. The onset of action is about 15 minutes, and it peaks in about one hour. Lispro lasts about 4 hours, so it gives you almost the same configuration as the absorption of carbohydrates from a meal – a significant theoretical advantage.  Premixed Insulins  70/30 – consists of 70 parts NPH and 30 parts regular  75/25 – consists of 75 parts NPH 25 parts humalog.  Specific programs or regimens that we have for type 1 diabetics:  There is a tendency for the blood sugar to drop around 2:00AM and then spontaneously rise prior to waking (called the dawn phenomenon).  The most simplistic program is intermediate-acting insulin given once a day.  This does not deal with the postprandial hyperglycemia, and it doesn't deal with the AM hyperglycemia. These patients will come in with high blood sugars; by the afternoon, they are doing pretty well, but you lose the control in the morning.  You can improve the above program by adding a second dose of intermediate-acting insulin, the so called split dose regimen. It could be NPH or lente. Give the morning dose to control the afternoon blood sugar and give the evening dose to control the morning blood sugar .  The problem with this regimen is that you get a mismatch at 2AM; the patient has a tendency to develop a low blood sugar, yet you are getting a peak of the intermediate dose at that same time.  For years people have tried all sorts of thing to get around this: beefing up their bedtime snack, adding to the snack substances which delay carbohydrate absorption, etc. But the 2AM hypoglycemia is still a problem.  Furthermore, the program doesn't deal with meal-related hyperglycemia. You can do that by adding short acting insulin (regular or Lispro) to the morning shot and the evening shot; that helps to control the blood sugar rise after breakfast and the suppertime blood sugar rise. But this regimen doesn’t deal with the lunchtime rise in glucose concentration.  There are also the premixes you can use, the 70/30 or the 75/25. It gives you a little bit better control over the morning blood sugar and over the evening blood sugar than the others, but it does not get rid of the mismatch at 2AM. This is a major limitation of these regimens.  The whole point is to control these patients on an individual basis.  A major improvement in the split mix regimen is to move the evening NPH from suppertime to bedtime. This is a program that was developed for pregnant women with diabetes because of the tendency to develop hypoglycemia in the middle of the night. The fetus is consuming glucose, and these patients really bottom out. By moving the insulin later in the day, you get less of a mismatch at 2AM and some spillover of the insulin into the morning, and it is much better tolerated. So what these patients do is take NPH or Lente plus a short acting insulin in the morning , a short acting insulin at supper time, and then a third dose of NPH or Lente at bedtime; this is the standard "intensive" insulin regimen you will see used on type 1 diabetic patients.  The next step for these patients is the ultralente, which we don't use too much because it is inconsistently absorbed. Glargine will hopefully replace ultralente and provide us with this monotonic and predictable amount of insulin throughout the day.

5  Or we can use insulin pumps, which basically do the same thing, even in a better way. They are expensive, but they allow us to set this baseline wherever we want it; then we superimpose short acting insulin before each meal for postprandial glucose control. This is the Cadillac, or the best regimen. Back to Case 2  Now to illustrate what happens when you take all of these insulins as this patient was: although the insulins are being taken as discrete injections, they all have lengthy half-lives in circulation, so you get a relatively consistent level of insulin throughout the day and throughout the night.  Type 1 diabetics are exquisitely sensitive to insulin – a little too much and they become hypoglycemic, a little too little and they become ketoacidotic. We really have to run them close to this critical insulin level to protect them from either extreme.  The morning of the surgery he was told not to take his insulin, so his insulin level went to zero a few hours thereafter. He took a puny dosage of Humalog at suppertime that night after he got home from the surgery; he was headed for ketoacidosis right there. When he called the ENT doctor and told him about the nausea and vomiting, he was in ketoacidosis, not an anesthetic reaction. So type 1 diabetics will go into DKA if not given some insulin, even if they can't eat. In this sense they are insulin dependent.  The term insulin dependent is often misused to include all diabetics who are receiving insulin, but many of these are type 2 diabetics; we should call these type 2 patients insulin requiring, not insulin dependent. The word dependent implies ketoacidosis prone; it is only in this sense that type 1 diabetics are insulin dependent.  In order to give enough insulin to protect against ketoacidosis, you may actually have to give them glucose intravenously. If this patient had gone in to get his tonsillectomy, and the doctor didn't want him to take his whole insulin dosage, he should have given him the insulin with glucose – this would have prevented the ketoacidosis as well as hypoglycemia. Usually the program is to give 30-50% of the long acting insulin that the patient normally takes plus a glucose infusion as necessary.  Ketosis is fairly common in type 1 diabetics, but ketoacidosis is very uncommon. Most of the patients who have repeated episodes of ketoacidosis are simply not checking for early ketosis; most of the time it is because they don't understand that they really need to. They think that testing the urine is somehow or another archaic or dirty. They also don’t understand that they are not checking for sugar in the urine, but ketones. They need to be taught that there is a big difference between having a high blood sugar, which may have long-term adverse effects and having ketones, which is going to have a short-term and very serious adverse effect. Summary:  Type 1 diabetes is usually an autoimmune disorder which results from the gradual destruction of pancreatic beta cells.  With severe insulin deficiency, ketoacidosis develops. In this sense, Type 1 diabetics are insulin dependent.  Although treatment of Type 1 diabetes arrests the catabolic process and produces symptomatic improvement, the objective of treatment is prevention of complications.  This can be accomplished for many patients by glucose control and attention to associated risk factors. Multiple insulin preparations and insulin regimens are available for the treatment of these patients.