BEATING DIABETES MELLITUS THROUGH MEDICAL INFORMATION MASTERY AND POEMs

 INTRO INTO DIABETES MELLITUS-THE INCONROVERTIBLE DISEASE

Diabetes Mellitus Diagnosis:  

As we have seen with Obesity and Hypertension (Past Two Articles for my Family Medicine Rotation and this article for my Jackson Park Rotation in Internal Medicine-attendant Dr. Murthy, M.D. Hospital Director), it was the little things in life, made as positive unconscious health habits, which when implemented can reverse said conditions through a life commitment for health.  As you will see, both obesity and hypertension control are essential elements in controlling diabetes.  However Diabetes and its various types have genetic or acquired links, receptor damage, cell damage necessary for the production of prime hormones affecting the insulin and glucagon worlds, which further complicate concepts of complete cure for even moderate to severe disease. 

Thus, Diabetes Mellitus is presently an incurable yet in many cases more manageable then previously (just the last decade) thought disease which is a major cause of premature death and disability within the United States.  As far back as 1997 and for that year alone, direct medical cost and lost-productivity was measured at $59 billions per year.  And has been rising ever since.  For an alarming example, Diabetes mellitus is on the rise in the United States in adolescents with an elevated BMI! 

A very interesting Surveillance survey relative to Diabetes Mellitus found for 1990 increased prevalence from prior years of 4.9 to 6.5% increase.  During that period, the sex-age-race adjusted prevalence increased in both genders, and the largest prevalence increases occurred in the 30-39 age category and higher education levels.  Finally, overall prevalence of Diabetes Mellitus increased another 6% one year later and was directly correlated with increased Obesity during the same period. 

Worldwide prevalence for DM has risen dramatically over the past two decades with the expectation that type 2 DM is expected to rise even more rapidly in the future because of increasing obesity and reduced activity levels.  Finally DM increases with aging. 

Antithetically, first we went through Obesity, then Hypertension which illustrated some consistent connections between both and understanding disease ramifications rendering either more controllable.  Now we must understand the various types of diabetes and the interrelationships between obesity, hypertension, hyperlipidemia and issues and events which will follow in this series.   However and again, first we must understand Diabetes Mellitus. 

Type 2 non-insulin-dependent DM represents 90% to 95% of all cases.  African-American, Hispanic and native America prevalence for type 2 DM is 1.3 to 3 times higher than Caucasians.  The usual onset for type 2 DM is in adults over the age of 40 and increases with age over 65.  A sub Variance of type 2 DM, maturity onset diabetes of youth, occurs below the age of 30 and usually in children.  And of course type 1 DM primarily involves our children.   

Defects in insulin secretion, insulin action or a combination are characterized by hyperglycemia.  Type 1 DM results from an absolute insulin deficiency, and type 2 DM is characterized by peripheral insulin resistance and either a relative insulin deficiency or a predominant insulin secretory defect that leads to hepatic glucose overproduction.

There are three well understood genetic and autoimmune cell damage that can lead to the main types of diabetes: 

·         Type 1 Diabetes Mellitus involves synergistic effects of genetic, environmental, and immunologic β-cell destruction.  If total insulin deficiency is not replaced with insulin, ketoacidosis, rapid dehydration, coma and death can ensue.

·         Type 2 Diabetes Mellitus involves defects in insulin action related to mutations of insulin receptors.  Here there is a progressive increase above normal of fasting and postprandial glucose levels with higher-than normal insulin levels caused by insulin resistance.  As the insulin resistance and glucose levels rise, insulin levels decline as β-cells are destroyed.  The process begins five to ten years prior to clinical symptomatology.  In many cases it takes 30 years for the β-cell destruction subsequent to the clinical symptoms arising.

·         Maturity onset diabetes of youth involves β-cell function with impaired insulin secretion in an Autosomal dominant inheritance with early onset of hyperglycemia.   It must be noted that autoimmune beta cell destructive processes can develop at any age. 

These defects in insulin action can occur peripherally which affects glucose uptake and storage in the muscle and/or the liver resulting with increased glucose production and is thus a vicious cycle with the end result known as insulin resistance.  

Gestational Diabetes Mellitus or glucose intolerance of pregnancy can develop related to the metabolic changes of late pregnancy which increase s insulin requirements and may lead to IGT.  GDM occurs in approximately 4% of pregnancies in the Unites States with most women reverting back to normal glucose tolerance post-partum but have a substantial risk (30-60) of developing DM later in life. 

Below is a more complete listing of causation for Diabetes Mellitus:

Etiologic Classification of Diabetes Mellitus

1        Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)

A.     Immune-mediated

B.     Idiopathic

2. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly insulin secretory defect with insulin resistance).
3. Other specific types of diabetes
   1. Genetic defects of β-cell function characterized by mutations in:

1.      Hepatocyte nuclear transcription factor (HNF) 4 α (MODY 1)

2.      Glucokinase (MODY 2)

3.      HNF-1 α (MODY3)

4.      Insulin promoter factor (IPF) 1 (MODY 4)

5.      HNF-1β (MODY 5)

6.      NeuroD1 (MODV6)

7.      Mitochondrial DNA

8.      Proinsulin or insulin conversion

     B.  Genetic defects in insulin action

                        1.  Type A insulin resistance

                        2.   Leprechaunism

                        3.  Rabson-Mendenhall syndrome

                        4.  Lipodystrophy syndromes

C. Diseases of exocrine pancreases such as pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy.

E.     Endocrinopathies such as acromegaly, Cushing’s syndrome,  glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma

F.     Infections such as congenital rubella, cytomegalovirus, and coxsackie

G.    Uncommon forms of immune-mediated diabetes – “stiff-man” syndrome, anti-insulin receptor antibodies.

H.    Other genetic syndromes sometimes associates with diabetes include Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome, wolfram’s syndrome, Friedreich’s ataxia, Huntington’s Chorea, Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, and Prader-Willi syndrome.

       4.  Gestational diabetes mellitus 

The diagnosis of Diabetes Mellitus can be established if any of three criteria are met.  These criteria follow: 

• Presence of the classic symptoms of diabetes, such as polyuria, polydipsia, ketonuria, and rapid weight loss, together with gross and unequivocal elevation of plasma glucose levels ≥ 11.1 mmol/L (200 mg/dL)…where random is defined as without regard to time since the last meal or
• Fasting plasma glucose ≥ 7.0 mmol/L (126 mg/dL) where fasting is defined as no caloric intake for at least 8 hours or
• Two-hour plasma glucose ≥ 11.1 mmol/L (200 mg/dL) during an oral glucose tolerance test.  The test should be performed using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved n water; not recommended for routine clinical use. 

In the absence of unequivocal hyperglycemia and acute metabolic decompensation, these criteria should be confirmed by repeat testing on a different day.

Most patients who are diabetic according to oral glucose tolerance also have fasting plasma glucose levels greater than 140 mg/dl.  It is wise to test individual with normal fasting blood glucose if there is a strong suspicion of diabetes, such as the presence of complications possibly secondary to diabetes, an extensive family history, or certain genetic characteristics and conditions.  In other words, the diagnosis of diabetes mellitus should rarely be made in the absence of fasting hyperglycemia.

Initial Evaluation:

Clearly from the complexity for causation of diabetes, clinical evaluation must include a thorough history, physical examination, and appropriate diagnostic testing.  With regard to type 2 DM, symptom onset is gradual, nonspecific, and mild.  Approximately one third of people with diabetes are undiagnosed!  It is therefore essential for clinicians to have a high index of suspicion for risk factors such as family history, along with the following signs and symptoms:

• General: weight loss, fatigue, chronic malaise, gradually increasing thirst
• Dermatolic; recurrent fungal infections (vaginal, dermatophytic, intertrigo, etc.), slow healing of skin injuries
• Ophthalmologic: recent visual changes (often requiring a change in refractive correction), blurred vision (caused by osmotic and fluid  changes in the lens due to hyperglycemia)
• Dental: periodontal disease
• Urinary: nocturnal and polyuria
• Neurologic: burning, tingling, numbness in feet and/or hands

The Elderly patient with type 2 DM may present acutely with confusion, lethargy, prostration, hypothermia, dehydration, hypotension/shock, and less commonly in a nonketotic coma cause by marked hyperglycemia (glucose level greater than 1,999mg/dL).  This syndrome is called hyperglycemic hyperosmolar nonketotic coma.

Relative to type 1 DM, acute presentation typically occurs during diabetic ketoacidosis.  Patients with type 1 DM, usually children or adolescents, report a rapid onset of some or all of the classic symptoms of diabetes; polyuria, polydipsia, polyphagia, weight loss, and fatigue.  There is even a seasonal incidence of type 1 DM which parallels that of viral infections, with of course more cases presenting in winter and early spring.

Finally no diabetic history would be complete absent evaluation for risk factors such as vascular complication.  Questioning along these lines would include smoking habits, previous blood pressure and lipid measurement, physical activity, and family history of cardiovascular disease.  One half of patients with diabetes have complications at diagnosis, assessment of current complication should include visual difficulties, periodontal disease, of course cardiovascular history, sexual dysfunction, and peripheral neuropathy.  Note prior ophthalmologic, dental or podiatric care.  It has been reported that a recent population-based epidemiology study found that the simple question, “Thinking now of both legs or both feet, have you had pain or discomfort such as numbness, burning, or tingling when you are walking in the past 6 months?” was a valuable predictor of the presence of peripheral neuropathy with a 97% sensitivity when compared with the gold standard of a formal neurologic examination by a neurologist.

Physical Examination:

Eleven specific areas for risk of diabetes have been identified by the American Diabetes Association and the American ‘Association of Clinical Endocrinologists and are now guidelines for the initial physical examination of a patient who is suspected to have diabetes which follow:

• Height and weight
• Blood pressure with ortostatic evaluation
• Ophthalmologic examination
• Oral examination, thyroid palpation
• Cardiac examination
• Evaluation of pulses
• Abdominal examination
• Hand/finger examination
• Feet examination
• Skin examination
• Neurologic examination includes reflexes, vibratory sensation, touch, and proprioception.

Please note that both "obesity" and "hypertension" are horrible risk factors and risk amplifiers for disease.  Obesity is a significant risk factor for type 2 DM as it aggravates insulin resistance.  Body Mass Indices >25 and < 30 designate obese. Abdominal adiposity, assessed with waist to hip ratio, is also an independent risk factor for Diabetes Mellitus hypertension and ischemic heart disease.

Hypertension is both an independent and co-risk factor for cardiovascular disease in Diabetes Mellitus patients.  Of course measure blood pressure in and out of the clinical setting to avoid “white coat” hypertension and on multiple occasions.  It has been recommended that blood pressure in diabetic patients be maintained below 130/85 and, if there is proteinuria (1 g/24h), below 125/75.

Retinopathy is the most frequent cause of new cases of blindness among adults between 20 and 74 years of age.  Retinopathy is also a microvascular complication of both type 1 and 2 DM.  Thus all patients with DM should have a retinal screening examination as part of the initial evaluation and annually thereafter.  Examination of the heart, peripheral pulses, feet and legs, and the peripheral neurologic system as well as dentition should be meticulously documented at initial evaluation.  These organs are targets of microvascular disease, and should be regularly reevaluated. 

For detection of the propensity to develop foot ulcers, the monofilament foot examination will identify patients at high risk for subsequent foot ulcer.  Compared with the measurement of pedal pulses, and vibration perception threshold, the monofilament examination had over 85% reproducibility between different examiners and different times and was the only test judged to be satisfactory for such utility.

Laboratory

By the age of 45, screening for type 2 DM is recommended for individuals at high risk of DM and, if there are no complications, is repeated at 3-year intervals.  Individuals with significant risk factors such as parents or sibling with DM, BMI>27, physical inactivity, racial predisposition, hypertension, elevated lipid levels, and previously identified impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), and for women with a history of gestational diabetes or delivery of a baby weighting greater than 9 lb or who have polycystic ovary syndrome, must have their laboratory evaluation at much earlier on.  Because of the increased incidence of type 2 DM in youth, over-weight children and adolescents should be screened at age 19, and every 2 years.

The criteria for IFG or IGT are as follows:

• IFG: fasting plasma glucose ≥ 110 and < 126 mg/dL (fasting is defined as no caloric intake for at least 8 hours), or
• IGT: 2-hour postload plasma glucose ≥ 140 and <200 mg/dL (a glucose load containing the equivalent of 75 g of anhydrous glucose dissolved n water).

Diagnosis criteria for DM in the non-pregnant adult follows as one of the following findings must be documented don at least two occasions, on separate days:

• A 2 hour plasma glucose ≥ 200 mg/dL
• A fasting plasma glucose ≥ 126 mg/dL
• A fasting plasma glucose <126 mg/dL, a high index of suspicion of DM, and a plasma glucose ≥ 200 performed on a different day.

The development of baseline levels to establish possible end-organ complications has been suggested by the American Diabetes Association and American Association for Clinical endocrinologists through measuring potassium, blood urea nitrogen, creatinine, and microalbuminuria and creatinine clearance, and performing both an electrocardiogram and a urinalysis.  Dyslipidemia is determined by the measurement of cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol), and triglycerides.

Relative to differential diagnosis although type 1 DM is most likely when ketoacidosis is found, patients with severe alcohol and less prevalent methanol intoxication present with ketosis.  Hyperglycemia absent ketoacidosis can accompany acute pain secondary to trauma, myocardial ischemia or infarction, or other critical illnesses, steroid us or Cushing’s disease, hypothyroidism, the infiltrative disease o iron overload known as hemochromatosis.

Relative to type 2 DM today science and clinical studies have revealed a link between MNT or medical nutritional therapy which is a healthy-eating plan that's naturally rich in nutrients and low in fat and calories, with an emphasis on fruits, vegetables and whole grains combined with proper exercise is the key.  In fact, a diabetes diet is the best eating plan for most folks.  The studies reveal that improper diet for a specific person's physiology over a life time cause insulin resistance, which begins a cascade of events leading to the high triglycerides, the high cholesterol, damage to the blood vessels, high blood pressure, metabolic imbalance accompanied causing the body to receive poor energy sources akin but not the same as starvation and being to break down the muscle glycogen stores, and eventually 80% of glucose comes from fat breakdown, more specifically from the glycerol backbone of triglycerides, which enters gluconeogenesis to create glucose through glyconeogenesis but further fat storage by excess insulin due to insulin resistance and hence, fat storage around the abdomen but small extremities due to lack of exercise and proper nutritional proteins and thus muscle loss.  This furthers the metabolic imbalances leading to the body resisting any weight loss. 

Treatment:

If the patient can become the principal manager of their own diabetes, the primary care physician and other members of the health care team become partners for a most successful outcome.  In this circumstance, the patient must have a good understanding of the disease and its complications and then adhering to the diet, exercise, weight control and/or reduction; self care that includes dental hygiene, foot care, avoiding tobacco, increasing physical activity, and modifying alcohol use; glucose monitoring, and medication compliance albeit maintaining an ideal body weight and an active lifestyle may prevent the onset of type 2 diabetes while currently there is no way to prevent type 1 diabetes. 

A systematic approach is required for the care of the diabetic patient.  Medical records reviewed, should allow the visual demonstration of baseline and follow-up data on glycemic control (Often times a complete dietary change must commence based on the MNT for that patient), end organ health, compliance with lifestyle modifications and medication, and the patient’s continued understanding of her disease and its management.

Today’s protocol requires the team approach to managing diabetes patients.  The Diabetes health care team usually is comprised of the primary care physician, nurse, dieticians and nutritionists, health educators, metal health counselors, and medical specialists including the endocrinologist, ophthalmologist, podiatrist, vascular surgeon, her family or social supports considered as a central part of the team. 

Monitoring Diabetic Control

Monitoring the glucose status helps the patient and physician understand the patients working physiology and live healthfully.  Usually diabetic control measures urine glucose concentrations at various times throughout the day.  The concentration of glucose in the urine depends on the renal threshold for glucose excretion, the renal blood flow, and the urine volume.  Home blood glucose monitoring, is the method of choice for monitoring diabetic control.  The accurate and routine measurement of home blood glucose levels by the education/informed patient is an essential ingredient in any intensive treatment regimen. 

Self-monitoring of blood glucose is accomplished by checking the glucose content of a drop of blood. Regular testing tells how well diet, medication, and exercise are working together to control the diabetes.

The results of the test can be used to adjust meals, activity, or medications to keep blood sugar levels in an appropriate range. Testing provides valuable information for the health care provider and identifies high and low blood sugar levels before serious problems develop.

The American Diabetes Association recommends that premeal blood sugar levels fall in the range of 80 to 120 mg/dL and bedtime blood levels fall in the range of 100 to 140 mg/dL.

Hemoglobin A1 assessment must be taught to the patient by the primary care physician.   The HbA1c is a measure of average blood glucose during the previous two to three months. It is a very helpful way to monitor a patient's overall response to diabetes treatment over time. A person without diabetes has an HbA1c around 5%. People with diabetes should try to keep it below 7%.

Ketone testing is another test that is used in type 1 diabetes. Ketones build up in the blood when there is not enough insulin in people with type 1 diabetes, eventually "spilling over" into the urine. The ketone test is done on a urine sample. High levels of blood ketones may ketoacidosis as previously discussed.  Ketone testing is usually done at the following times:

• When the blood sugar is higher than 240 mg/dL
• During acute illness (for example, pneumonia, heart attack, or stroke)
• When nausea or vomiting occur
• During pregnancy

Health Habit

The goals of medical nutritional therapy are to maintain near-normal blood glucose by balancing insulin or oral-glucose lowering medications with exercise and diet; to achieve optimal serum lipid levels and to maintain reasonable weight with calories and to prevent acute complications of insulin use and long-term microvascular and macrovascular complications.  It must be noted that moderate weight loss (10-20lbs) regardless of patient starting weight, is associated with reduced hyperglycemia, Dyslipidemia, and hypertension.

Medical nutrition therapy (MNT) is a term used to describe the optimal coordination of caloric intake with other aspects of diabetes therapy.  For example in patient with type 2 DM, although weight loss is a concomitant program within care, the focus of the MNT seeks to modify patient hyperlipidemia and hypertension.  Further glycemic control is also associated with correct dietary changes concomitant with aerobic fitness regardless of weight.  Weight loss strategies include moderate reduction of daily caloric intake, 250-500 calories, the appropriate nutritional intake, reduction of total fat and especially saturate fats, and increased physical activity.  Unless the patient is tested for food sensitivity which tailors the program to the individual, and of course has the most success the generalized daily caloric intake of protein, fat and carbohydrate components follow:

• Protein: 10% to 20%
• Carbohydrates: 50%-60%
• Fat: <30% (saturated fat<10%, polyunsaturated fat<10%, monounsaturated fat 10-15%).

Patients's with overt nephropathy should limit protein intake to 10% of total caloric intake.  It must be noted that saturated fats should be <10% of total calories with dietary cholesterol ≤ 300 mg daily.  If LDL is a consideration, saturated fats should be reduced below 7% and dietary cholesterol below 200 mg/d. 

Polyunsaturated fats in the form of the omega-3 series occurring naturally in fish and other seafood are acceptable for diabetic patients.  It is the total amount of carbohydrates consumed that is more important than the consumption of simple versus complex carbohydrates, and again the first importance is a changed diet away from lab proven sensitivities to gluten and other elements of the human diet which cause sensitivity reactions which break down the homeostasis of the patient. 

The goal of MNT in type 1 DM is to coordinate and match the caloric intact, both temporally and quantitatively, with the appropriate amount of insulin.  The goal of MNT in type 2 DM focus on reducing the prevalence of cardiovascular risk factors such as hypertension, Dyslipidemia, and obesity as well as the tailored diet away from lab proven food sensitivities. 

The majority of these patients are obese, and must be strongly encouraged to make unconscious good life habit eating and exercise habits. Current protocol for initial MNT care would emphasize modest caloric reduction, reduced fat intake, increased physical activity, and reduction of hyperlipidemia and hypertension.  Again soluble dietary fiber may improve glycemic control in type 2 DM patients but the priority of importance is to test for and then eliminate discovered food sensitivities.

In obese type II DM patients, the aims of diet management first and foremost which then aids in losing weight and controlling hyperglycemia (For MNT diet see Beating Obesity Through Medical Information Mastery and POEMs). The diet should meet the patient's minimum daily protein requirement (0.9 g/kg) and be designed to induce a gradual and sustained weight loss (about 2 lb/wk) until ideal body weight is approached and maintained.  Increased physical activity in sedentary obese type II DM patients is valuable and may decrease insulin resistance over time. Diabetics with hypertension should be treated with ACE inhibitors, which have been shown to be more protective against coronary artery disease than Ca channel blockers, until the dietary changes concomitant with exercise the lab values to normal or at least a normalization of Triglycerides, Cholesterol, Blood Pressure, Obesity and so forth.

Exercise

Examination focused on signs and symptoms of disease that adversely affect the cardiovascular system, eyes, kidneys, and nervous systems is correlated with the proposed exercise program individually tailored for the specific medical condition, age, current condition and taking into account jarring exercising vs. non-jarring exercises such as swimming.  Exercises which simulate a Valsalva like maneuvers must be avoided in patient with proliferate retinopathy and overt nephropathy (microalbuminuria>200 mg/min). Regular exercise is especially important for people with diabetes.  It helps with blood sugar control, weight loss, and high blood pressure.  People with diabetes who exercise are less likely to experience a heart attack or stroke than diabetics who do not exercise regularly

Of course exercise can be quite a challenge to some patients as not only must they overcome deconditioining associated with disease, it often feels at first like a challenge not yet faced.  When in reality, it is the very small repetition of exercise which can lead to longer and increased work exercise, which eventually will help cardiovascular risk reduction, reduced blood pressure, maintenance of muscle mass, reduction of body fat, and weight loss as well as lowering plasma glucose during and following exercise and increasing insulin sensitivity in both types 1 and 2 DM.  Obviously, monitoring of the patients pre, and post exercise glucose status and when and how much carbohydrate to ingest to prevent hypoglycemia is mandatory.   As the patient is able to self check and maintain glycemic control, much in the way of disease symptomatology and manifestations can abate.

Foot Care

People with diabetes are prone to foot problems because of the likelihood of damage to blood vessels and nerves and a decreased ability to fight infection. Problems with blood flow and damage to nerves may cause an injury to the foot to go unnoticed until infection develops. Death of skin and other tissue can occur.

If left untreated, the affected foot may need to be amputated. Diabetes is the most common condition leading to amputations.

To prevent injury to the feet, people with diabetes should adopt a daily routine of checking and caring for the feet as follows:

• Check your feet every day, and report sores or changes and signs of infection.
• Wash your feet every day with lukewarm water and mild soap, and dry them thoroughly.
• Soften dry skin with lotion or petroleum jelly.
• Protect feet with comfortable, well-fitting shoes.
• Exercise daily to promote good circulation.
• See a podiatrist for foot problems or to have corns or calluses removed.
• Remove shoes and socks during a visit to your health care provider and remind him or her to examine your feet.
• Stop smoking, which hinders blood flow to the feet

HOW TO TAKE INSULIN OR ORAL MEDICATION

Human insulin is often preferred in initiating insulin treatment because it is less antigenic than animal-derived varieties. However, detectable insulin antibody levels, usually very low, develop in most insulin-treated patients, including those receiving human insulin preparations.

Insulin is routinely provided in preparations containing 100 U/mL (U-100 insulin) and is injected subcutaneously with disposable insulin syringes. The 1/2-mL syringes are generally preferred by patients who routinely inject doses of <= 50 U, because they can be read more easily and facilitate the accurate measurement of smaller doses. A multiple-dose insulin injection device (NovolinPen), commonly referred to as an insulin pen, is designed to use a cartridge containing several days' dosage. Insulin should be refrigerated but never frozen; however, most insulin preparations are stable at room temperature for months, which facilitates their use at work and when traveling.

Insulin preparations are classified as short-acting (rapid-acting), intermediate-acting, or long-acting. The critical determinant of the onset and duration of action of an insulin preparation is the rate of insulin absorption from the injection site.

Rapid-acting insulins include regular insulin, which is a preparation of zinc insulin crystals in a suspending solution; regular insulin is the only insulin preparation that can be given IV. Lispro, a form of regular insulin that is genetically engineered with a substitute of one amino acid, provides more rapid absorption of insulin and therefore may be administered with food. Semilente insulin is slightly slower rapid-acting insulin, containing zinc insulin microcrystals in an acetate buffer. Intermediate-acting insulin includes neutral protamine Hagedorn, which contains a stoichiometric mixture of regular, and protamine zinc insulin, and Lente, which contains 30% Semilente insulin and 70% Ultralente insulin in an acetate buffer. Long-acting protamine zinc insulin contains insulin that is negatively charged, combined with an excess of positively charged fish sperm protamine. Ultralente contains large zinc insulin crystals in an acetate buffer.

Mixtures of insulin preparations with different onsets and durations of action are frequently given in a single injection by drawing measured doses of two preparations into the same syringe immediately before use. The manufacturers recommend that Semilente be mixed only with Lente or Ultralente to maintain the same buffer solution. However, individual doses of regular insulin and neutral protamine Hagedorn or Lente insulin are commonly drawn up into the same syringe to combine rapid- and intermediate-acting insulin in a single injection. A preparation that contains a mixture of 70% neutral protamine Hagedorn and 30% regular human semisynthetic insulin (Novolin 70/30 or Humulin 70/30) is also available, but its fixed ratio of intermediate- to rapid-acting insulin may restrict its use. Protamine zinc insulin must always be injected separately, because it contains an excess of protamine.

Initiation of insulin therapy in adults:

In DCCT, type I DM patients received an average total dose of about 40 U insulin a day. Because type II DM patients are insulin resistant, they require more insulin. Thus, those who are severely hyperglycemic and obese may be started on about 40 U of insulin per day. The initial total daily dose may be divided so that 1/2 will be administered before breakfast, 1/4 before dinner, and 1/4 at bedtime. Because of severe insulin resistance, type II DM patients may need twice that much and often more. After the initial dose is selected, adjustments in the amounts, types, and timing are made based on plasma glucose determinations. The dose is adjusted to maintain preprandial plasma glucose between 80 and 150 mg/dL (4.44 and 8.33 mmol/L). Increments in insulin dose are generally restricted to 10% at a time, and the effects are assessed over about 3 days before any further increment is made. More rapid adjustments of regular insulin are indicated if hypoglycemia threatens.

Initiation of insulin therapy in children:

Children who present at an early stage of type I DM with moderate hyperglycemia but without ketonuria or acidosis may be started with a single daily subcutaneous injection of 0.3 to 0.5 U/kg of intermediate-acting insulin alone. Children who present with both hyperglycemia and ketonuria but who are not acidotic or dehydrated may be started on 0.5 to 0.7 U/kg of intermediate-acting insulin and then supplemented by subcutaneous injections of 0.1 U/kg of regular insulin at 4- to 6-h intervals. Insulin doses are usually adjusted to maintain preprandial plasma glucose levels between 80 and 150 mg/dL (4.44 and 8.33 mmol/L) or sometimes between 80 and 120 mg/dL (4.44 and 6.66 mmol/L).

Insulin schedules:

The goal of insulin therapy is to control hyperglycemic surges after meals and to provide baseline levels that support normal glucose metabolism. Regimens must always be individualized, and some diabetics will achieve tight control with highly idiosyncratic schedules. However, the approach should include:

1. Bedtime intermediate-acting insulin. This helps control nocturnal hepatic glucose production. Starting the day with lower morning glucose levels will improve glucose tolerance throughout the day. Bedtime insulin is associated with less weight gain than is daytime insulin alone. Bedtime insulin is also a reasonable way to initiate insulin therapy in type II DM patients who are not controlled by oral drugs alone.
2. Before-breakfast mixed insulin. This often is accomplished with a mixture of about 30% short-acting and 70% intermediate-acting insulin. Most diabetic patients will need about half the daily insulin dose before breakfast.
3. Before-lunch-and-dinner regular insulin. For tight control, supplemental rapid-acting insulin should be taken before meals. The dose should be taken 15 to 30 min before a meal for regular or Semilente and with a meal for Lispro.

Multiple subcutaneous insulin injections:

These are designed to maintain normal or near-normal plasma glucose levels throughout the day in patients with type I DM. Such treatment may increase the risks for frequent and severe episodes of hypoglycemia. Patients should be highly motivated, well educated in DM, informed of the risks and uncertain benefits, competent in self-monitoring of glucose, and under the supervision of a physician experienced in its use. In a typical multiple subcutaneous insulin injection regimen, about 25% of the total daily dose is given as intermediate-acting insulin at bedtime, with additional doses of rapid-acting insulin given before each meal (a four-dose regimen). Type I DM patients may require intermediate- or long-acting insulin in the morning to give coverage throughout the day. The patient adjusts daily dosage on the basis of self-monitoring of glucose before each meal and at bedtime; the plasma glucose level between 2 and 4 am is assessed at least once/wk.

Continuous subcutaneous insulin infusion:

This mode of intensive insulin treatment in patients with type I DM involves a small battery-powered infusion pump that provides a continuous subcutaneous infusion of rapid-acting insulin through a small needle, usually inserted in the abdominal wall. The pump is programmed to infuse a selected basal rate of insulin, supplemented by manually triggered or programmed increased rates before each meal. The patient measures glucose levels several times a day to adjust the dosage. Control obtainable with this method is superior to that obtained with multiple injections. Hypoglycemic episodes are common with pump therapy, especially during the establishment of metabolic control. However, once metabolic control is established, pumps are not associated with more hypoglycemia than are multiple injections. Experimental pump implants and intraperitoneal deliveries of insulin to the portal system may prove superior. However, the indwelling needle increases the risk of infections at needle sites.

Insulin treatment of brittle diabetes:

Brittle diabetics are type I DM patients who exhibit frequent, rapid swings in glucose levels without apparent cause.

Brittle diabetes is most common in patients with no residual insulin secretory capacity. The metabolic processes through which insulin affects the plasma levels of glucose, albumin-bound free fatty acids, and ketones are normally regulated by shifts in the balance between the effects of insulin and the opposing effects of glucagon (in the liver) and the adrenergic autonomic nervous system. These counter regulatory mechanisms are independently regulated and normally increased during fasting, exercise, and other conditions that require protection against hypoglycemia. Insulin doses must be adequate to deal with a sudden increase in counter regulatory mechanisms and to prevent rapidly developing symptomatic hyperglycemia and hyperketonemia, but this frequently produces transient plasma insulin excess.

Many of these patients improve when switched to a modified multiple subcutaneous insulin regimen that provides most of the daily insulin as rapid-acting insulin in daily adjusted dosages before each meal, with some intermediate-acting insulin in the morning, before the evening meal, or at bedtime. The aim is not to maintain the diurnal plasma glucose level in a near-normal range but to stabilize the fluctuations in a range that prevents symptomatic hyper- and hypoglycemia.

Complications of insulin treatment:

Hypoglycemia occurs because of an error in insulin dosage, a small or missed meal, or unplanned exercise (patients are usually instructed to reduce their insulin dose or to increase their carbohydrate intake before planned exercise) or without apparent cause. Patients are taught to recognize symptoms of hypoglycemia, which usually respond rapidly to the ingestion of sugar. All diabetics should carry candy, lumps of sugar, or glucose tablets. An identification card, bracelet, or necklace indicating that the patient is an insulin-treated diabetic aids in recognizing hypoglycemia in emergencies. Close family members should be instructed to administer glucagon with an easy-to-use injection device. Emergency medical personnel, after confirming the hypoglycemia with a glucostick, should initiate therapy with a rapid bolus injection of 25 mL of 50% glucose solution followed by a continuous IV infusion of glucose.

The dawn phenomenon refers to the normal tendency of the plasma glucose to rise in the early morning hours before breakfast, which is frequently exaggerated in patients with type I DM and in some patients with type II DM. Fasting glucose levels rise because of an increase in hepatic glucose production, which may be secondary to the midnight surge of growth hormone. In some patients with type I DM, nocturnal hypoglycemia may be followed by a marked increase in fasting plasma glucose with an increase in plasma ketones (Somogyi phenomenon). Thus, both the dawn and Somogyi phenomena are characterized by morning hyperglycemia, but the latter is due to rebound (counter regulation) hyperglycemia. The frequency with which the latter phenomenon actually occurs is disputed. When it is suspected, the patient should wake between 2 and 4 am to monitor blood glucose levels. If intermediate insulin is administered at bedtime, the dawn and Somogyi phenomena can often be prevented.

Local allergic reactions at the site of insulin injections are less common with purified porcine and human insulins. These reactions can produce immediate pain and burning, followed after several hours by local erythema, pruritus, and induration, the latter sometimes persisting for days. Most reactions spontaneously disappear after weeks of continued insulin injection and require no specific treatment, although antihistamines are sometimes used.

Generalized insulin allergy (usually to the insulin molecule) is rare but can occur when treatment is discontinued and restarted after a lapse of months or years. Such reactions may occur with any type of insulin, including human biosynthetic insulin. Symptoms usually develop shortly after an injection and may include urticaria, angioedema, pruritus, bronchospasm, and, in some cases, circulatory collapse. Treatment with antihistamines may suffice, but epinephrine and IV glucocorticoids may be required. If continued insulin treatment is required after the condition stabilizes, skin testing with a panel of purified insulin preparations and desensitization should be performed by an experienced physician.

Insulin resistance is an increase in insulin requirement to ≥ 200 U/day and is associated with marked increases in the plasma insulin-binding capacity. Most patients treated with insulin for > 6 mo develop antibodies to insulin. The relative antigenicity of purified insulin preparations is bovine > porcine > human, but genetic factors also affect individual response. Circulating insulin-binding antibodies can modify the pharmacokinetics of free insulin, but treatment usually is not adversely affected. In patients with insulin resistance, switching to purified porcine or human insulin may lower the requirement. Remission may be spontaneous or may be induced in some type II DM patients who can stop insulin treatment for 1 to 3 mo. Prednisone may decrease insulin requirements within 2 wk; treatment is usually initiated with about 30 mg bid and is tapered as the requirements decrease.

Local fat atrophy or hypertrophy at injection sites is relatively rare and usually improves by switching to human insulin and injecting it directly into the affected area. No specific treatment of local fat hypertrophy is required, but injection sites should be rotated.

Oral antidiabetic drugs:

These drugs are used for type II DM but not for type I DM because they cannot prevent symptomatic hyperglycemia or DKA in such patients. Oral hypoglycemic drugs are the sulfonylureas. Oral antihyperglycemic drugs are the biguanides, the -glucosidase inhibitors, and the insulin sensitizers (thiazolidinediones ["glitazones"]).

Sulfonylureas:

The sulfonylureas lower plasma glucose primarily by stimulating insulin secretion. Secondary effects on improving peripheral and hepatic insulin sensitivity may be due to the decrease in both glucose toxicity and insulin clearance. Sulfonylureas differ in potency and duration of action. All of the sulfonylureas are metabolized in the liver, but only tolbutamide and tolazamide are inactivated exclusively by the liver. About 30% of chlorpropamide is normally excreted in the urine, and the principal hepatic metabolite of acetohexamide is highly active and excreted in urine; both drugs carry an increased risk of prolonged hypoglycemia in patients with impaired renal function and in the elderly. The 2nd-generation sulfonylureas (such as glipizide and glyburide) are about 100 times more potent than the 1st-generation ones, are absorbed rapidly, and are metabolized mainly in the liver. Clinically, the 2nd-generation sulfonylureas are similar in effectiveness.

Allergic reactions and other side effects (e.g., cholestatic jaundice) are relatively uncommon. Acetohexamide may be used in patients who are allergic to other sulfonylureas. Chlorpropamide and acetohexamide should not be used in patients with impaired renal function. In addition, chlorpropamide should not be used in elderly patients, because it can potentiate the action of antidiuretic hormone, often leading to hyponatremia and deterioration in mental status, which in an elderly patient may often not be recognized as a drug-induced effect.

For the initial treatment, many authorities prefer the shorter-acting sulfonylureas, and most do not recommend using a combination of different sulfonylureas. Treatment is started with a low dose, which is adjusted after several days until a satisfactory response is obtained or the maximum recommended dosage is reached. About 10 to 20% of patients fail to respond to a trial of treatment (primary failures), and patients who fail to respond to one sulfonylurea often fail to respond to others. Of patients who initially respond, 5 to 10% per year experience secondary failures. In such cases, insulin may be added to sulfonylurea treatment.

Hypoglycemia is the most important complication of sulfonylurea treatment. Hypoglycemia can occur in patients treated with any of the sulfonylureas but occurs most frequently with long-acting ones (glyburide, chlorpropamide). Sulfonylurea-induced hypoglycemia can be severe and may last or recur for days after treatment is stopped, even when it occurs in patients treated with tolbutamide, whose usual duration of action is 6 to 12 h. A mortality rate of 4.3% in patients hospitalized with sulfonylurea-induced hypoglycemia has been reported recently. Therefore, all sulfonylurea-treated patients who develop hypoglycemia should be hospitalized, because even if they respond rapidly to initial treatment for hypoglycemia, they must be closely monitored for 2 to 3 days. Most of these patients may not require further treatment with sulfonylureas.

Antihyperglycemic drugs:

Metformin (a biguanide) has been used as primary therapy in type II DM patients for over 30 years in most of the world. It has been recently approved for use in the USA. It acts by decreasing hepatic glucose production and may improve insulin sensitivity in those who lose weight. It is as effective as a sulfonylurea as monotherapy (when used alone it rarely causes hypoglycemia) and is synergistic in combination with sulfonylurea therapy. Metformin also promotes weight loss and decreases lipid levels. Unlike phenformin, metformin rarely causes severe lactic acidosis. GI side effects are common, but often transient, and may be prevented if the drug is taken with meals and if the dosage is gradually increased (by 500 mg/wk up to 2.5 g). Metformin is contraindicated in patients with kidney and liver diseases or alcoholism. It is also contraindicated in patients with lactic acidosis and should be withheld during acute hospitalization in most patients.

Acarbose is an -glucosidase inhibitor that competitively inhibits hydrolysis of oligo- and monosaccharides. This delays carbohydrate digestion in the small intestine and subsequent absorption, resulting in less postprandial elevation of blood glucose levels. Because its mechanism of action differs from that of other oral hypoglycemics, it can be used in combination therapy with other oral agents. GI side effects are very common, but often transient. The drug must be taken with meals, and the dosage should be gradually increased from 25 mg up to 50 to 100 mg with each meal.

Thiazolidinediones are the insulin-sensitizer drugs that improve insulin sensitivity in skeletal muscle and suppress hepatic glucose output. The only such drug available in the USA is troglitazone. It has been recently approved for use in the treatment of type II DM patients requiring insulin and has moderate effects on decreasing plasma glucose and triglyceride levels. This drug is administered once a day and has potentially idiosyncratic hepatotoxicity. Patients should be instructed to decrease their daily insulin dosage with the initiation of therapy.

Diabetes Management during hospitalization:

Diabetic patients admitted to hospitals commonly have coexisting illnesses that aggravate hyperglycemia, such as an infection or coronary artery disease. Bed rest and a regular diet may also aggravate hyperglycemia. Conversely, if the patient is anorectic or vomits, or if food intake is reduced, continuation of drugs may cause hypoglycemia. The popular insulin coverage with a sliding scale for insulin administration should not be the only intervention, because it is reactive rather than proactive in correcting hyperglycemia. It may also be inappropriately used when hyperglycemia reflects hepatic gluconeogenesis in response to previously uncorrected hypoglycemia.

Hospitalized type II DM patients often do well without any change in drugs. Hypoglycemic drugs may be discontinued during an acute condition associated with decreased food intake or one that has a tendency to cause hypoglycemia. Insulin may be added if plasma glucose levels remain high.

In type I DM patients, intermediate (NPH or Lente) insulin should be continued at 50 to 70% of the daily dose divided bid or tid. Supplemental regular insulin can be given on a sliding scale. In patients receiving total or partial parenteral nutrition, hyperglycemia may be treated with a continuous IV infusion of insulin or divided doses of intermediate-acting insulin. Blood glucose should be measured four times a day before meals.

Diabetes Management during surgical procedures:

Surgical procedures (including the prior emotional stress, the effects of general anesthesia, and the trauma of the procedure) can markedly increase plasma glucose in diabetics and induce DKA in type I DM patients. In patients who normally take one or two daily injections of insulin, 1/3 to 1/2 of the usual morning dose can be given in the morning before the operation and an IV infusion of 5% glucose in either 0.9% sodium chloride solution or water at a rate of 1 L (50 g of glucose) over 6 to 8 h started. After the operation, plasma glucose and the plasma reaction for ketones are checked. Unless a change in dosage is indicated, the preoperative dose of insulin is repeated when the patient has recovered from the anesthesia and the glucose infusion is continued. Plasma glucose and ketones are monitored at 2- to 4-h intervals, and regular insulin is given q 4 to 6 h as needed to maintain the plasma glucose level between 100 and 250 mg/dL (5.55 and 13.88 mmol/L). This is continued until the patient can be switched to oral feedings and a one- or two-dose insulin schedule.

Some physicians prefer to withhold subcutaneous insulin on the day of the operation and to add 6 to 10 U of regular insulin to 1 L of 5% glucose in 0.9% sodium chloride solution or water infused initially at 150 mL/h on the morning of the operation based on the plasma glucose level. This is continued through recovery, with insulin adjusted based on the plasma glucose levels obtained in the recovery room and at 2- to 4-h intervals thereafter.

Insulin is not required for diabetics who have maintained a satisfactory plasma glucose level by diet alone or in combination with a sulfonylurea before the operation. Sulfonylureas should be withheld 2 to 4 days before the operation, and plasma glucose levels should be measured pre- and postoperatively and q 6 h while patients receive IV fluids.

Chronic Evaluation:

Diabetes Mellitus is a chronic disease that requires long-term therapy for successful long-term management.  Much akin to hypertension control over blood pressure and obesity management, it has become clear that maintenance therapy is important for long-term success with the DM patient until all food sensitivities have been eliminated and the patient's own natural system regulation again returns to normal.  This is not always achievable but more and more research say's its probable for many.  Thus reevaluation with their primary care physician or chronic evaluation ensures the most “spot on” immediate understanding of base line data and allows flexibility for the patient while offering the greatest protection against end organ disease, multiple system disease, and best chance to improve and reverse disease in mild cases.  Patients must regain control over their unconscious health habits which will reduce or prevent hypertension, obesity, and adult onset related disease.  For those with Diabetes Mellitus, it is now clear that these very same health habits will help the patient control their disease, reduce detrimental effects and improve the patients overall life experience.

In conclusion, after the initial treatment plan duration return for Chronic Evaluation has been proved by the evidence to help the patient maintain their glucose control, for the best life one can experience while combating their Diabetes Mellitus.

Medical Text References:

1. Sloane, Philip D et al, Essentials of Family Medicine, 4^th Edition, Lippincott-Williams & Wilkins, pages 453-470
2. Andreoli Thomas E et al, Cecil Essentials of Medicine, 4^th Saunders, pages 513-523.
3. Kasper Dennis L et al, Harrison’s Principles of Internal Medicine, 16^th edition, Mc Graw Hill, pages 2152-2180
4. Beers, Mark H et al, The Merc Manual of Diagnosis and Therapy, 17^th Edition, Merck Research Laboratories, pages 165-177
5. Brunton Laurence L et al, Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11^th edition, Mcgraw-Hill, pages 113-125

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