DIABETES MELLITUS



T R E A T M E N T R E P O R T

Diabetes Mellitus

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Treatment Regimens

A. Diet

1. American Diabetes Association (ADA) recommendations

2. Dietary fiber

3. Artificial sweeteners

B. Oral Drugs for Treating Hyperglycemia

1. Drugs that stimulate insulin secretion

2. Drugs that alter insulin action

3. Drugs that affect absorption of glucose

4. Drug combinations

5. Safety of the oral hypoglycemic agents

C. Incretins

D. Insulin

1. Characteristics of available insulin preparations

2. Insulin preparations

3. Methods of insulin administration

E. Transplantation

General Considerations in the Treatment of Diabetes

Steps in the Management of the Diabetic Patient

A. Diagnostic Examination

B. Patient Education (Self-Management Training)

C. Initial Therapy

1. 1. Type 2 diabetes

2. 2. Type 1 diabetes

Acceptable Levels of Glycemic Control

Prognosis

Treatment Regimens

A. Diet

A well-balanced, nutritious diet remains a fundamental element of therapy. However, in more than half of cases, diabetic patients fail to follow their diet. In prescribing a diet, it is important to relate dietary objectives to the type of diabetes. In obese patients with mild hyperglycemia, the major goal of diet therapy is weight reduction by caloric restriction. Thus, there is less need for exchange lists, emphasis on timing of meals, or periodic snacks, all of which are so essential in the treatment of insulin-requiring nonobese diabetics. This type of patient represents the most frequent challenge for the clinician. Weight reduction is an elusive goal that can only be achieved by close supervision and education of the obese patient.

1. American Diabetes Association (ADA) recommendations

The ADA releases an annual position statement on medical nutrition therapy that replaces the calculated ADA diet formula of the past with suggestions for an individually tailored dietary prescription based on metabolic, nutritional, and lifestyle requirements. They contend that the concept of one diet for "diabetes" and the prescription of an "ADA diet" no longer can apply to both major types of diabetes. In their recommendations for persons with type 2 diabetes, the 55-60% carbohydrate content of previous diets has been reduced considerably because of the tendency of high carbohydrate intake to cause hyperglycemia, hypertriglyceridemia, and a lowered HDL cholesterol. In obese type 2 patients, glucose and lipid goals join weight loss as the focus of therapy. These patients are advised to limit their carbohydrate content by substituting noncholesterologenic monounsaturated oils such as olive oil, rapeseed (canola) oil, or the oils in nuts and avocados. This maneuver is also indicated in type 1 patients on intensive insulin regimens in whom near-normoglycemic control is less achievable on higher carbohydrate diets. They should be taught "carbohydrate counting" so they can administer 1 unit of regular insulin or insulin lispro for each 10 or 15 g of carbohydrate eaten at a meal. In these patients, the ratio of carbohydrate to fat will vary among individuals in relation to their glycemic responses, insulin regimens, and exercise pattern.

The current recommendations for both types of diabetes continue to limit cholesterol to 300 mg daily and advise a daily protein intake of 10-20% of total calories. They suggest that saturated fat be no higher than 8-9% of total calories with a similar proportion of polyunsaturated fat and that the remainder of caloric needs be made up of an individualized ratio of monounsaturated fat and of carbohydrate containing 20-35 g of dietary fiber. Poultry, veal, and fish continue to be recommended as a substitute for red meats for keeping saturated fat content low. The present ADA position statement proffers no evidence that reducing protein intake below 10% of intake (about 0.8 g/kg/d) is of any benefit in patients with nephropathy and renal impairment, and doing so may be detrimental.

Exchange lists for meal planning can be obtained from the American Diabetes Association and its affiliate associations or from the American Dietetic Association, 216 W. Jackson Blvd., Chicago, IL 60606 (312-899-0040). Their Internet address is .

2. Dietary fiber

Plant components such as cellulose, gum, and pectin are indigestible by humans and are termed dietary "fiber." Insoluble fibers such as cellulose or hemicellulose, as found in bran, tend to increase intestinal transit and may have beneficial effects on colonic function. In contrast, soluble fibers such as gums and pectins, as found in beans, oatmeal, or apple skin, tend to retard nutrient absorption rates so that glucose absorption is slower and hyperglycemia may be slightly diminished. Although its recommendations do not include insoluble fiber supplements such as added bran, the ADA recommends food such as oatmeal, cereals, and beans with relatively high soluble fiber content as staple components of the diet in diabetics. High soluble fiber content in the diet may also have a favorable effect on blood cholesterol levels.

3. Artificial sweeteners

Aspartame (NutraSweet) has proved to be a popular sweetener for diabetic patients. It consists of two amino acids (aspartic acid and phenylalanine) that combine to produce a nutritive sweetener 180 times as sweet as sucrose. A major limitation is that it cannot be used in baking or cooking because of its lability to heat.

The nonnutritive sweetener saccharin continues to be available in certain foods and beverages despite warnings by the Food and Drug Administration (FDA) about its potential long-term carcinogenicity to the bladder. The latest position statement of the ADA concludes that all nonnutritive sweeteners that have been approved by the FDA (such as aspartame and saccharin) are safe for consumption by all people with diabetes. Two other nonnutritive sweeteners have been approved by the FDA as safe for general use: sucralose (Splenda) and acesulfame potassium (Sunett, Sweet One, DiabetiSweet). These are both highly stable and, in contrast to aspartame, can be used in cooking and baking.

Nutritive sweeteners such as sorbitol and fructose have increased in popularity. Except for acute diarrhea induced by ingestion of large amounts of sorbitol-containing foods, their relative risk has yet to be established. Fructose represents a "natural" sugar substance that is a highly effective sweetener and induces only slight increases in plasma glucose levels. However, because of potential adverse effects of large amounts of fructose (up to 20% of total calories) on raising serum cholesterol and LDL cholesterol, the ADA feels it may have no overall advantage as a sweetening agent in the diabetic diet. This does not preclude, however, ingestion of fructose-containing fruits and vegetables or fructose-sweetened foods in moderation.

B. Oral Drugs for Treating Hyperglycemia

(Tables 27-7, 27-8, and 27-9.) The drugs for treating type 2 diabetes fall into three categories: (1) Drugs that primarily stimulate insulin secretion: Sulfonylureas remain the most widely prescribed drugs for treating hyperglycemia. The meglitinide analog repaglinide and the d-phenylalanine derivative nateglinide also bind the sulfonylurea receptor and stimulate insulin secretion. (2) Drugs that alter insulin action: Metformin works primarily in the liver. The thiazolidinediones appear to have their main effect on skeletal muscle and adipose tissue. (3) Drugs that principally affect absorption of glucose: The Α-glucosidase inhibitors acarbose and miglitol are such currently available drugs.

Table 27-7. Oral antidiabetic drugs that stimulate insulin secretion.

|Drug |

|    Tolbutamide (Orinase) |

|    Repaglinide (Prandin) |

|    Nateglinide (Starlix) |

|    Metformin (Glucophage) |

|    Rosiglitazone (Avandia) |

|    Acarbose (Precose) |50 and 100 mg |75-300 mg in 3 divided doses with |4 hours |

| | |first bite of food | |

|Rapid-acting insulin analogs |

|    Insulin lispro (Humalog, Lilly) |Human analog |U100 |$67.58 |

| |(recombinant) | | |

|    Insulin aspart (Novolog, Novo Nordisk) |Human analog |U100 |$74.88 |

| |(recombinant) | | |

|    Insulin glulisine (Apidra, Sanofi Aventis) |Human analog |U100 |  |

| |(recombinant) | | |

|Short-acting regular insulins |

|    "Purified"2 |

|        Regular Novolin (Novo Nordisk)3 |Human |U100 |$30.50 |

|        Regular Humulin (Lilly) |Human |U100, U500 20 mL |$29.28, $210.68 |

|        Regular Iletin II (Lilly) |Pork |U100 |$47.98 |

|Intermediate-acting insulins |

|    "Purified"2 |

|        Lente Humulin (Lilly) |Human |U100 |$29.28 |

|        Lente Iletin II (Lilly) |Pork |U100 |$47.98 |

|        Lente Novolin (Novo Nordisk)3 |Human |U100 |$30.50 |

|        NPH Humulin (Lilly) |Human |U100 |$29.28 |

|        NPH Iletin II (Lilly) |Pork |U100 |$47.98 |

|        NPH Novolin (Novo Nordisk)3 |Human |U100 |$30.50 |

|Premixed insulins |

|    % NPH/% regular |

|        Novolin 70/30 (Novo Nordisk)3 |Human |U100 |$30.50 |

|        Humulin 70/30 and 50/50 (Lilly) |Human |U100 |$29.28 |

|    Other Mixes |

|        75% insulin lispro protamine/25% |Human analog |U100 (insulin pen, prefilled |Pen $144.63, Vial |

|insulin lispro (Humalog Mix 75/25 [Lilly]) |(recombinant) |syringes, 5 × 3-mL cartridges) |$71.88 |

|        70% insulin aspart protamine/30% |Human analog |U100 (insulin pen, prefilled |Pen $144.62, Vial |

|insulin aspart (Novolog Mix 70/30 [Novo |(recombinant) |syringes, 5 × 3-mL cartridges) |$74.88 |

|Nordisk]) | | | |

|Long-acting insulins |

|    "Purified"2 |

|        Ultralente Humulin (Lilly) |Human |U100 |$29.28 |

|        Insulin glargine (Lantus, Aventis) |Human analog |U100 |$66.85 |

| |(recombinant) | | |

1All of these agents (except insulin lispro and U500) are available without a prescription. Average wholesale price (AWP, for AB-rated generic when available) for 10-mL vial unless otherwise specified. Source: Red Book Update, Vol. 24, No. 4, April 2005. Wholesale prices for all human preparations (except insulin lispro and U500) are similar. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.

2Less than 10 ppm proinsulin.

3Novo Nordisk human insulins are termed Novolin R, L, and N.

Rapid-acting insulin analogs and regular insulin are dispensed as clear solutions at neutral pH and contain small amounts of zinc to improve their stability and shelf life. The long-acting insulin analog insulin glargine is also dispensed as a clear solution but at acidic pH. Other intermediate-acting and long-acting insulins are dispensed as turbid suspensions at neutral pH with either protamine in phosphate buffer (NPH insulin) or varying concentrations of zinc in acetate buffer (ultralente and lente insulins). The rapid-acting insulin analogs, intermediate-acting, and long-acting insulins are designed for subcutaneous administration only, while regular insulin can also be given intravenously.

a. Rapid-acting insulins

Insulin lispro (Humalog) is an insulin analog produced by recombinant technology, wherein two amino acids near the carboxyl terminal of the B chain have been reversed in position: Proline at position B28 has been moved to B29 and lysine has been moved from B29 to B28. Insulin aspart (Novolog) is a single substitution of proline by aspartic acid at position B28. Insulin glulisine (Apidra) differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 by glutamic acid. These changes result in these three analogs having less tendency to form hexamers, in contrast to human insulin. When injected subcutaneously, the analogs quickly dissociate into monomers and are absorbed very rapidly, reaching peak serum values in as soon as 1 hour-in contrast to regular human insulin, whose hexamers require considerably more time to dissociate and become absorbed. The amino acid changes in these analogs do not interfere with their binding to the insulin receptor, with the circulating half-life, or with their immunogenicity, which are all identical with those of human regular insulin.

Clinical trials have demonstrated that the optimal times of preprandial subcutaneous injection of comparable doses of the rapid-acting insulin analogs and of regular human insulin are 20 minutes and 60 minutes, respectively, before the meal. While this more rapid onset of action has been welcomed as a great convenience by diabetic patients who object to waiting as long as 60 minutes after injecting regular human insulin before they can begin their meal, patients must be taught to ingest adequate absorbable carbohydrate early in the meal to avoid hypoglycemia during the meal. Another desirable feature of insulin lispro is that its duration of action remains at about 4 hours irrespective of dosage. This contrasts with regular insulin, whose duration of action is prolonged when larger doses are used.

Table 27-11. Examples of intensive insulin regimens using rapid-acting insulin analogs (insulin lispro, aspart, or glulisine) and ultralente, NPH, or insulin glargine in a 70-kg man with type 1 diabetes.1-3

|  |Pre-Breakfast |Pre-Lunch |Pre-Dinner |At Bedtime |

|Rapid-acting insulin analog |5 units |4 units |6 units |- |

|Ultralente insulin |8 units |- |8 units |- |

|  |  |OR |  |  |

|Rapid-acting insulin analog |5 units |4 units |6 units |- |

|NPH insulin |3 units |3 units |2 units |8-9 units |

|  |  |OR |  |  |

|Rapid-acting insulin analog |5 units |4 units |6 units |- |

|Insulin glargine |- |- |- |15-16 units |

1Assumes that patient is consuming approximately 75 g carbohydrate at breakfast, 60 g at lunch, and 90 g at dinner.

2The dose of insulin lispro or insulin aspart can be raised by 1 or 2 units if extra carbohydrate (15-30 g) is ingested or if premeal blood glucose is > 170 mg/dL. Insulin lispro or insulin aspart can be mixed in the same syringe with ultralente or NPH insulin.

3Insulin glargine cannot be mixed with any of the available insulins and must be given as a separate injection.

b. Short-acting regular insulin

Regular insulin is a short-acting soluble crystalline zinc insulin whose effect appears within 30 minutes after subcutaneous injection and lasts 5-7 hours when usual quantities are administered. Intravenous infusions of regular insulin are particularly useful in the treatment of diabetic ketoacidosis and during the perioperative management of insulin-requiring diabetics. When intravenous insulin is needed for hyperglycemic emergencies, the rapid-acting insulin analogs have no advantage over regular human insulin, which is instantly converted to the monomeric form when given intravenously. Regular insulin is indicated when the subcutaneous insulin requirement is changing rapidly, such as after surgery or during acute infections-although the rapid-acting insulin analogs may be preferable in these situations.

The rapid-acting analogs are also commonly used in pumps. In a double-blind crossover study comparing insulin lispro with regular insulin in insulin pumps, persons using insulin lispro had lower HbA1c values and improved postprandial glucose control with the same frequency of hypoglycemia. The concern remains that in the event of pump failure, users of the rapid-acting insulin analogs will have more rapid onset of hyperglycemia and ketosis.

c. Intermediate-acting insulins

Lente insulin is a mixture of 30% semilente (an amorphous precipitate of insulin with zinc ions) with 70% ultralente insulin (an insoluble crystal of zinc and insulin). Its onset of action is delayed for up to 2 hours, and because its duration of action often is less than 24 hours (with a range of 18-24 hours), most patients require at least two injections daily to maintain a sustained insulin effect. Lente insulin has its peak effect in most patients between 8 and 12 hours, but individual variations in peak response time must be considered when interpreting unusual or unexpected patterns of glycemic responses in individual patients. NPH (neutral protamine Hagedorn or isophane) insulin is an intermediate-acting insulin whose onset of action is delayed by combining 2 parts soluble crystalline zinc insulin with 1 part protamine zinc insulin. This produces equivalent amounts of insulin and protamine, so that neither is present in an uncomplexed form ("isophane").

The onset and duration of action of NPH insulin are comparable to those of lente insulin; it is usually mixed with regular insulin and given at least twice daily for insulin replacement in type 1 patients. Occasional vials of NPH insulin have tended to show unusual clumping of their contents or "frosting" of the container, with considerable loss of bioactivity. This instability is rare and occurs less frequently if NPH human insulin is refrigerated when not in use and if bottles are discarded after 1 month of use.

d. Long-acting insulins

Humulin ultralente is a crystalline insulin whose duration of action is less than that of the previously available beef ultralente. It is generally recommended that the daily dose be split into two equal doses given 12 hours apart. Its peak is less than that of NPH insulin, and it is often used to provide basal coverage while the short-acting insulins are used to cover the glucose rise associated with meals.

Insulin glargine is an insulin analog in which the asparagine at position 21 of the A chain of the human insulin molecule is replaced by glycine and two arginines are added to the carboxyl terminal of the B chain. The arginines raise the isoelectric point of the molecule closer to neutral, making it more soluble in an acidic environment. In contrast, human insulin has an isoelectric point of pH 5.4. Insulin glargine is a clear insulin which, when injected into the neutral pH environment of the subcutaneous tissue, forms microprecipitates that slowly release the insulin into the circulation. It lasts for about 24 hours without any pronounced peaks and is given once a day to provide basal coverage. This insulin cannot be mixed with the other human insulins because of its acidic pH. When this insulin was given as a single injection at bedtime to type 1 patients, fasting hyperglycemia was better controlled when compared with bedtime NPH insulin. The clinical trials also suggest that there may be less nocturnal hypoglycemia with this insulin when compared with NPH insulin.

In one clinical trial involving type 2 patients, insulin glargine was associated with a slightly higher progression of retinopathy when compared with NPH insulin. The frequency was 7.5% with the analog and 2.7% with the NPH. This finding, however, was not seen in other clinical trials with this analog. Insulin glargine does have a sixfold greater affinity for IGF-1 receptor compared with the human insulin. There has also been a report that insulin glargine had increased mitogenicity compared with human insulin in a human osteosarcoma cell line. The significance of these observations is not yet clear. Because of lack of safety data, use of insulin glargine during pregnancy is not recommended.

e. Mixtures of insulin

Since intermediate insulins require several hours to reach adequate therapeutic levels, their use in type 1 patients requires supplements of regular or lispro insulin preprandially. It is well established that insulin mixtures containing increased proportions of lente to regular insulins may retard the rapid action of admixed regular insulin. The excess zinc in lente insulin binds the soluble insulin and partially blunts its action, particularly when a relatively small proportion of regular insulin is mixed with lente (e.g., 1 part regular to 1.5 or more parts lente). NPH preparations do not contain excess protamine and so do not delay absorption of admixed regular insulin. They are therefore preferable to lente when mixtures of intermediate and regular insulins are prescribed. For convenience, regular and NPH insulin may be mixed together in the same syringe and injected subcutaneously in split dosage before breakfast and supper. It is recommended that the regular insulin be withdrawn first, then the NPH insulin. No attempt should be made to mix the insulins in the syringe, and the injection is preferably given immediately after loading the syringe. Stable premixed insulins (70% NPH and 30% regular or 50% of each) are available as a convenience to patients who have difficulty mixing insulin because of visual problems or impairment of manual dexterity.

With increasing use of rapid-acting insulin analogs as a popular and convenient preprandial insulin, it has become evident that combination with a more sustained insulin is essential to maintain postabsorptive glycemic control. It has been demonstrated that the rapid-acting insulin analogs can be acutely mixed with NPH without affecting their rapid absorption. Insulin lispro can also be mixed with ultralente insulin. Premixed preparations of insulin lispro and NPH insulins are unstable because of exchange of insulin lispro with the human insulin in the protamine complex. Consequently, the soluble component becomes over time a mixture of regular and insulin lispro at varying ratios. In an attempt to remedy this, an intermediate insulin composed of isophane complexes of protamine with insulin lispro was developed called NPL (neutral protamine lispro). This insulin has the same duration of action as NPH insulin. Premixed combinations of NPL and insulin lispro (eg, 75:25, 50:50, and 25:75 of NPL:insulin lispro) have been tested. The 75% NPL:25% insulin lispro mixture (Humalog Mix 75/25) is available for clinical use. Similarly, a 70% insulin aspart protamine/30% insulin aspart (NovoLogMix 70/30) is now available. The main advantages of these new mixtures is that they can be given within 15 minutes of starting a meal and they are superior in controlling the postprandial glucose rise after a carbohydrate rich meal. These benefits have not translated into improvements in HbA1c levels when compared with the usual 70% NPH/30% regular mixture.

3. Methods of insulin administration

a. Insulin syringes and needles

Plastic disposable syringes are available in 1-mL, 0.5-mL, and 0.3-mL sizes. The "low-dose" 0.3-mL syringes have become increasingly popular, because many diabetics do not take more than 30 units of insulin in a single injection except in rare instances of extreme insulin resistance. Two lengths of needles are available: short (8 mm) and long (12.7 mm). Long needles are preferable in obese patients to reduce variability of insulin absorption. Ultrafine needles as small as 31 gauge reduce the pain of injections. "Disposable" syringes may be reused until blunting of the needle occurs (usually after three to five injections). Sterility adequate to avoid infection with reuse appears to be maintained by recapping syringes between uses. Cleansing the needle with alcohol may not be desirable since it can dissolve the silicone coating and can increase the pain of skin puncturing.

Any part of the body covered by loose skin can be used, such as the abdomen, thighs, upper arms, flanks, and upper buttocks. Preparation with alcohol is no longer required prior to injection as long as the skin is clean. Rotation of sites continues to be recommended to avoid delayed absorption when fibrosis or lipohypertrophy occurs from repeated use of a single site. However, considerable variability of absorption rates from different sites, particularly with exercise, may contribute to the instability of glycemic control in certain type 1 patients if injection sites are rotated too frequently in different areas of the body. Consequently, it is best to limit injection sites to a single region of the body and rotate sites within that region. The abdomen is recommended for subcutaneous injections, since regular insulin has been shown to absorb more rapidly from there than from other subcutaneous sites. The effect of anatomic regions appears to be much less pronounced with the analog insulins.

b. Insulin pen injector devices

Insulin pens eliminate the need for carrying insulin vials and syringes. Cartridges of insulin lispro, insulin aspart, insulin glargine, regular insulin, NPH insulin, and 70% NPH/30% regular insulin are available for reusable pens (Novo Nordisk, Becton Dickinson, and Sanofi Aventis pens). Disposable prefilled pens are also available for insulin lispro, NPH, 70% NPH/30% regular, 75% NPL/25% insulin lispro, and 70% insulin aspart protamine/30% insulin aspart. Thirty-one gauge needles (5, 6, and 8 mm long) for these pens make injections almost painless.

c. Insulin pumps

In the United States, Medtronic Mini-Med, Animas, and Deltec Cozmo insulin infusion pumps are available for subcutaneous delivery of insulin. These pumps are small (about the size of a pager) and very easy to program. They offer many features, including the ability to set a number of different basal rates throughout the 24 hours and to adjust the time over which bolus doses are given. They also are able to detect pressure build-up if the catheter is kinked. Improvements have also been made in the infusion sets. The catheter connecting the insulin reservoir to the subcutaneous cannula can be disconnected, allowing the patient to remove the pump temporarily (e.g., for bathing). The great advantage of continuous subcutaneous insulin infusion (CSII) is that it allows for establishment of a basal profile tailored to the patient. The patient therefore is able to eat with less regard to timing because the basal insulin infusion should maintain constant blood glucose between meals. Also the ability to adjust the basal insulin infusion makes it easier for the patient to manage glycemic excursions that occur with exercise.

CSII therapy is appropriate for patients who are motivated, mechanically inclined, educated about diabetes (diet, insulin action, treatment of hypoglycemia and hyperglycemia), and willing to monitor their blood glucose four to six times a day. Known complications of CSII include ketoacidosis, which can occur when insulin delivery is interrupted, and skin infections. Another disadvantage is its cost and the time demanded of physicians and staff in initiating therapy.

d. Inhaled insulin

A novel method for delivering preprandial insulin by inhalation has been reported. A 12-week study in type 1 patients showed that inhaled insulin is as efficacious as subcutaneously delivered insulin without additional side effects. Patients required 300-400 units of insulin a day, since only 10% of the inhaled insulin is bioavailable. Safety studies are in progress to determine whether long-term use affects pulmonary tissues.

E. Transplantation

Pancreas transplantation at the time of renal transplantation is becoming more widely accepted. Patients undergoing simultaneous pancreas and kidney transplantation have an 85% chance of pancreatic graft survival and a 92% chance of renal graft survival after 1 year. Solitary pancreatic transplantation in the absence of a need for renal transplantation should be considered only in those rare patients who fail all other insulin therapeutic approaches and who have frequent severe hypoglycemia or who have life-threatening complications related to their lack of metabolic control.

Islet cell transplantation is a minimally invasive procedure, and investigators in Edmonton, Canada, have reported initial insulin independence in a small number of patients with type 1 diabetes who underwent this procedure. Using islets from multiple donors and corticosteroid-free immunosuppression, percutaneous transhepatic portal vein transplantation of islets was achieved in over 20 subjects. Although all of the initial cohort was able to achieve insulin independence posttransplantation (some for more than 2 years of follow-up), a decline in insulin secretion has occurred over time and the subjects have again required supplemental insulin. All patients had complete correction of severe hypoglycemic reactions, leading to a marked improvement in overall quality of life. Even if long-term insulin independence is demonstrated, wide application of this procedure for the treatment of type 1 diabetes is limited by the dependence on multiple donors and the requirement for potent long-term immunotherapy.

General Considerations in Treatment of Diabetes

Insulin-treated patients with diabetes can have a full and satisfying life. However, "free" diets and unrestricted activity are still not advised. Until new methods of insulin replacement are developed that provide more normal patterns of insulin delivery in response to metabolic demands, multiple feedings with carbohydrate counting will continue to be recommended, and certain occupations potentially hazardous to the patient or others will continue to be prohibited because of risks due to hypoglycemia. The American Diabetic Association can act as a patient advocate in case of employment questions.

Exercise increases the effectiveness of insulin, and moderate exercise is an excellent means of improving utilization of fat and carbohydrate in diabetic patients. A judicious balance of the size and frequency of meals with moderate regular exercise can often stabilize the insulin dosage in diabetics who tend to slip out of control easily. Strenuous exercise can precipitate hypoglycemia in an unprepared patient, and diabetics must therefore be taught to reduce their insulin dosage in anticipation of strenuous activity or to take supplemental carbohydrate. Injection of insulin into a site farthest away from the muscles most involved in exercise may help ameliorate exercise-induced hypoglycemia, since insulin injected in the proximity of exercising muscle may be more rapidly mobilized.

All diabetic patients must receive adequate instruction on personal hygiene, especially with regard to care of the feet, skin, and teeth. All infections (especially pyogenic ones) provoke the release of high levels of insulin antagonists such as catecholamines or glucagon and thus bring about a marked increase in insulin requirements. Supplemental regular insulin is often required to correct hyperglycemia during infection.

Steps in the Management of the Diabetic Patient

A. Diagnostic Examination

Any features of the clinical picture that suggest end-organ insensitivity to insulin, such as visceral obesity, must be identified. The family history should document not only the incidence of diabetes in other members of the family but also the age at onset, whether it was associated with obesity, and whether insulin was required. Other factors that increase cardiac risk, such as smoking history, presence of hypertension or hyperlipidemia, or oral contraceptive pill use, should be recorded.

Laboratory diagnosis should document fasting plasma glucose levels above 126 mg/dL or postprandial values consistently above 200 mg/dL and whether ketonuria accompanies the glycosuria. A glycohemoglobin measurement is useful for assessing the effectiveness of future therapy. Some flexibility of clinical judgment is appropriate when diagnosing diabetes mellitus in the elderly patient with borderline hyperglycemia.

Baseline values include fasting plasma triglycerides, total cholesterol and HDL-cholesterol, electrocardiography, renal function studies, peripheral pulses, and neurologic, podiatric, and ophthalmologic examinations to help guide future assessments.

B. Patient Education (Self-Management Training)

Since diabetes is a lifelong disorder, education of the patient and the family is probably the most important obligation of the clinician who provides initial care. The best persons to manage a disease that is affected so markedly by daily fluctuations in environmental stress, exercise, diet, and infections are the patients themselves and their families. The "teaching curriculum" should include explanations by the physician or nurse of the nature of diabetes and its potential acute and chronic hazards and how they can be recognized early and prevented or treated. Self-monitoring of blood glucose should be emphasized, especially in insulin-requiring diabetic patients, and instructions must be given on proper testing and recording of data. Patients should be provided with algorithms they can use to adjust the timing and quantity of their insulin dose, food, and exercise in response to measured blood glucose values. The targets for blood glucose control should be elevated appropriately in elderly patients since they have the greatest risk if subjected to hypoglycemia and the least long-term benefit from more rigid glycemic control. Advice on personal hygiene, including detailed instructions on foot care as well as individual instruction on diet and specific hypoglycemic therapy, should be provided. Patients should be told about community agencies, such as Diabetes Association chapters, that can serve as a continuing source of instruction. Finally, vigorous efforts should be made to persuade new diabetics who smoke to give up the habit, since large vessel peripheral vascular disease and debilitating retinopathy are less common in nonsmoking diabetic patients.

C. Initial Therapy

Treatment must be individualized on the basis of the type of diabetes and specific needs of each patient. However, certain general principles of management can be outlined for hyperglycemic states of different types.

1. Type 2 diabetes

a. The obese type 2 patient

The most common type of diabetic patient is obese, is non-insulin-dependent, and has hyperglycemia because of insensitivity to normal or elevated circulating levels of insulin.

(1) Weight reduction

Treatment is directed toward achieving weight reduction, and prescribing a diet is only one means to this end. Behavior modification to achieve adherence to the diet-as well as increased physical activity to expend energy-is also required. Cure can be achieved by reducing adipose stores, with consequent restoration of tissue sensitivity to insulin, but weight reduction is hard to achieve and even more difficult to maintain with our current therapies. The presence of diabetes with its added risk factors may motivate the obese diabetic to greater efforts to lose weight.

(2) Hypoglycemic agents

Monotherapy with metformin (or Α-glucosidase inhibitors) is the first-line therapy in the obese patient with mild diabetes if pharmacotherapy is required since they are not associated with weight gain or drug-induced hypoglycemia. If metformin therapy (combined with a weight reduction regimen) is inadequate to control blood glucose levels, then a thiazolidinedione or a sulfonylurea should be added. Some individuals may require metformin, a thiazolidinedione, and a sulfonylurea to achieve adequate glycemic control.

Insulin therapy should be instituted if the combination of these three drugs fails to restore euglycemia. Weight-reducing interventions should continue and may allow for simplification of this regimen in the future.

b. The nonobese type 2 patient

In the nonobese diabetic, mild to severe hyperglycemia is usually due to refractoriness of B cells to glucose stimulation. Treatment depends on whether insulinopenia is mild (type 2 or mild type 1 in partial remission) or severe, with ketoacidosis.

(1) Diet therapy-

If hyperglycemia is mild, normal metabolic control can occasionally be restored by means of multiple feedings of a diet limited in simple sugars and with a caloric content sufficient to maintain ideal weight. Restriction of saturated fats and cholesterol is also strongly advised.

(2) Oral hypoglycemic agents

When diet therapy in nonketotic type 2 patients is not sufficient to correct hyperglycemia, a trial of sulfonylureas is often successful in reducing the glycohemoglobin concentration below 9.5%. Once the dosage of one of the more potent sulfonylureas reaches the upper recommended limit in a compliant patient without maintaining fasting blood glucose below 140 mg/dL during the day, combination therapy with metformin (up to 1000 mg twice daily) or a thiazolidinedione-or both-should be tried. When the patient fails the combination of these three drugs, insulin therapy is indicated.

c. Treatment of type 2 diabetes with insulin

When the combination of metformin, sulfonylurea, and a thiazolidinedione fails and patients with type 2 diabetes require insulin, various insulin regimens may be effective. A single nighttime injection of NPH or insulin glargine can be added and titrated to achieve target fasting blood glucose values while continuing the oral antidiabetic medications. If the patient does not achieve target glucose levels during the day, daytime insulin treatment can be initiated. A convenient insulin regimen under these circumstances is a split dose of 70/30 NPH/regular mixture (or Humalog Mix 75/25 or NovoLogMix 70/30) before breakfast and before dinner. If this regimen fails to achieve satisfactory glycemic goals or is associated with unacceptable frequency of hypoglycemic episodes, then a more intensive regimen of multiple insulin injections can be instituted. Metformin principally reduces hepatic glucose output and the thiazolidinediones improve peripheral resistance, and it is a reasonable option to continue these drugs when insulin therapy is instituted. The sulfonylureas also have been shown to be of continued benefit. Thus, the continued use of the oral drugs may permit the use of lower doses of insulin and simpler regimens.

2. Type 1 diabetes

Traditional once- or twice-daily insulin regimens are usually ineffective in type 1 patients without residual endogenous insulin. In these patients, information and counseling based on the findings of the DCCT should be provided about the advantages of taking multiple injections of insulin in conjunction with self-blood glucose monitoring. If near-normalization of blood glucose is attempted, at least three or four measurements of capillary blood glucose and three or four insulin injections are necessary.

A combination of rapid-acting insulin analogs and long-acting insulins (ultralente or insulin glargine) allows for more physiologic insulin replacement. The rapid-acting insulin analogs have been advocated as a safer and much more convenient alternative to regular human insulin for preprandial use. In a study comparing regular insulin with insulin lispro, daily insulin doses and hemoglobin A1c levels were similar, but insulin lispro improved postprandial control, reduced hypoglycemic episodes, and improved patient convenience compared with regular insulin. However, because of their relatively short duration (no more than 3-4 hours), the rapid-acting insulin analogs need to be combined with longer-acting insulins to provide basal coverage and avoid hyperglycemia prior to the next meal. In addition to carbohydrate content of the meal, the effect of simultaneous fat ingestion must also be considered a factor in determining the ultra-fast-acting insulin dosage required to control the glycemic increment during and just after the meal. With low-carbohydrate content and high-fat intake, there is an increased risk of hypoglycemia from insulin lispro within 2 hours after the meal. Table 27-11 illustrates some regimens that might be appropriate for a 70-kg person with type 1 diabetes eating meals providing standard carbohydrate intake and moderate to low fat content.

Table 27-12. Prebreakfast hyperglycemia: Classification by blood glucose and insulin levels.

|  |Blood Glucose (mg/dL) |  |  |Free Immunoreactive Insulin |

| | | | |(microunit/mL) |

  |10:00 PM |3:00 AM |7:00 AM |10:00 PM |3:00 AM |7:00 AM | | | |Somogyi effect |90 |40 |200 |High |Slightly high |Normal | | | |Dawn phenomenon |110 |110 |150 |Normal |Normal |Normal | | | |Waning of insulin dose plus dawn phenomenon |110 |190 |220 |Normal |Low |Low | | | |Waning of insulin dose plus dawn phenomenon plus Somogyi effect |110 |40 |380 |High |Normal |Low | | | |Multiple injections of NPH insulin (or twice-daily ultralente insulin) can be mixed in the same syringe as the insulin lispro, insulin aspart, and insulin glulisine. Insulin glargine is usually given once in the evening to provide 24-hour coverage. This insulin cannot be mixed with any of the other insulins and must be given as a separate injection. There are occasional patients in whom insulin glargine does not seem to last for 24 hours, and in such cases it needs to be given twice a day.

Continuous subcutaneous insulin infusion (CSII) by portable battery-operated "open loop" devices currently provides the most flexible approach, allowing the setting of different basal rates throughout the 24 hours and permitting patients to delay or skip meals and vary meal size and composition. The dosage is usually based on providing 50% of the estimated insulin dose as basal and the remainder as intermittent boluses prior to meals. For example, a 70-kg man requiring 35 units of insulin per day may require a basal rate of 0.7 units per hour throughout the 24 hours with the exception of 3 am to 8 am, when 0.8 units per hour might be appropriate (for the dawn phenomenon). The meal bolus would depend on the carbohydrate content of the meal and the premeal blood glucose value. One unit per 15 g of carbohydrate plus 1 unit for 50 mg/dL of blood glucose above a target value (eg, 120 mg/dL) is a common starting point. Further adjustments to basal and bolus dosages would depend on the results of blood glucose monitoring. The majority of patients use the rapid-acting insulin analogs in the pumps. One of the more difficult therapeutic problems in managing patients with type 1 diabetes is determining the proper adjustment of insulin dose when the prebreakfast blood glucose level is high. Occasionally, the prebreakfast hyperglycemia is due to the Somogyi effect, in which nocturnal hypoglycemia leads to a surge of counterregulatory hormones to produce high blood glucose levels by 7 am. However, a more common cause for prebreakfast hyperglycemia is the waning of circulating insulin levels by the morning. Also, the "dawn phenomenon"-reduced tissue sensitivity to insulin between 5 am and 8 am-is present in as many as 75% of type 1 patients and can aggravate the hyperglycemia.

Table 27-12 shows that diagnosis of the cause of prebreakfast hyperglycemia can be facilitated by self-monitoring of blood glucose at 3 am in addition to the usual bedtime and 7 am measurements. This is required for only a few nights, and when a particular pattern emerges from monitoring blood glucose levels overnight, appropriate therapeutic measures can be taken. The Somogyi effect can be treated by eliminating the dose of intermediate insulin at dinnertime and giving it at a lower dosage at bedtime or by supplying more food at bedtime. When a waning insulin level is the cause, then either increasing the evening dose or shifting it from dinnertime to bedtime (or both) can be effective. A bedtime dose either of insulin glargine or of NPH insulin made from pork insulin provides more sustained overnight insulin levels than human NPH or human ultralente insulin and may be effective in managing refractory prebreakfast hyperglycemia. If this fails, insulin pump therapy may be required. When the dawn phenomenon alone is present, the dosage of intermediate insulin can be divided between dinnertime and bedtime; when insulin pumps are used, the basal infusion rate can be increased (e.g., from 0.8 unit/h to 0.9 unit/h from 6 am until breakfast).

Acceptable Levels of Glycemic Control

See above for a discussion of the DCCT and the UKPDS and their implications for diabetes therapy. A reasonable aim of therapy is to approach normal glycemic excursions without provoking severe or frequent hypoglycemia. What has been considered "acceptable" control includes blood glucose levels of 90-130 mg/dL before meals and after an overnight fast, and levels no higher than 180 mg/dL 1 hour after meals and 150 mg/dL 2 hours after meals. Glycohemoglobin levels should be no higher than 1% above the upper limit of the normal range for any particular laboratory. It should be emphasized that the value of blood pressure control was as great as or greater than glycemic control in type 2 patients as regards microvascular as well as macrovascular complications.

Prognosis

The DCCT showed that the previously poor prognosis for as many as 40% of patients with type 1 diabetes is markedly improved by optimal care. DCCT participants were generally young and highly motivated and were cared for in academic centers by skilled diabetes educators and endocrinologists who were able to provide more attention and services than are usually available. Improved training of primary care providers may be beneficial.

For type 2 diabetes, the UKPDS documented a reduction in microvascular disease with glycemic control, although this was not apparent in the obese subgroup. Cardiovascular outcomes were not improved by glycemic control, although antihypertensive therapy showed benefit in reducing the number of adverse cardiovascular complications as well as in reducing the occurrence of microvascular disease among hypertensive patients. In patients with visceral obesity, successful management of type 2 diabetes remains a major challenge in the attempt to achieve appropriate control of hyperglycemia, hypertension, and dyslipidemia. Once safe and effective methods are devised to prevent or manage obesity, the prognosis of type 2 diabetes with its high cardiovascular risks should improve considerably.

In addition to poorly understood genetic factors relating to differences in individual susceptibility to development of long-term complications of hyperglycemia, it is clear that in both types of diabetes, the diabetic patient's intelligence, motivation, and awareness of the potential complications of the disease contribute significantly to the ultimate outcome.

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American Association of Diabetes Educators

American Diabetes Association

American Dietetic Association

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Source: Current Medical Diagnosis and Treatment 2006

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