Type 1 Diabetes

Patients with type 1 diabetes have an absolute require-ment of insulin for survival. This also applies to patients with diabetes resulting from total or near-total D-cell depletion, as seen in chronic pancreatitis. Insulin is also used by patients with type 2 diabetes when combinationoral agents fail to achieve glucose targets and temporarily in some patients during serious infections or surgery. Up to 58 % of patients with type 2 diabetes eventually require exogenous insulin. Seventy-six percent of all patients taking insulin have type 2 diabetes. In women with gestational diabetes, when diet and exercise fail to achieve acceptable blood glucose control, insulin is required because oral antihyperglycemic agents are contraindicated in pregnancy.

Most insulin preparations are manufactured enzymatically or by recombinant DNA technology, and most are available at a concentration of 100 U/mL (U-100). Based on pharmaco-dynamic properties, the types of insulin currently available are rapid-acting, short-acting, intermediate-acting, and long-act-ing preparations(Table 35). Insulin therapy is usually started in the outpatient setting unless Dt(A is the initial presentation of type 1 diabetes. Multiple different insulin regimens exist. The regimen of bedtime insulin (NPH) and daytime sulfo-ny-lurea therapy (BIDS) has been successful in patients with type 2 diabetes as regular therapy or as a transition stage from oral antidiabetic therapy to total insulin therapy.

Standard insulin therapy consists of one to two injections per day using intermediate-acting or long-acting insulin with or without regular or lispro insulin. This approach provides sim-plicity, relative safety, and ease of compliance. Premixed in-sulins such as 70/30 (70% NPH/30% regular) or 50/50, usually administered twice daily, provide ease of use are less likely to achieve good glycemic control. A split or mixed regi-men of NPH/regular or NPH/lispro twice daily (two thirds of the calculated total dialy dose before breakfast and one third before dinner; at each time two thirds NPH and one third reg-ular or lispro) dictates regular mealtimes and insulin injections.

Intensive insulin therapy refers to multiple (three or more) daily injections, using combinations of insulins, such as regular or lispro insulins three times daily, and justed before meals, and NPH at bedtime, or through continuous subcuta-neous insulin infusion. By more closely approximating normal physiologic insulin delivery, patients are able to achieve glycemic control and increasing lifestyle flexibility. NPH should be given at least 30 minutes before a meal and can be mixed with regular insulin in the same syringe. Ultralente in-sulin can be given in combination with regular insulin, but it should not be mixed in the same syringe because the zinc in the ultralente insulin delays the absorption of the regular insulin.

Calculating insulin dosages is still empirical. Starting dos-es of insulin vary from 0.15 to 0.5 U/(kg'day) depending on patient size and degree of glycemia, and they may ultimately be as high as 1.5 U/kg in patients with severe insulin resis-tance. The calculated total daily insulin requirement is then di-vided according to the administration regimen chosen. In gen-eral, 40% to 50% of the total daily dose provides basal re-quirements, and the remainder is divided between meals in a manner proportionate to the relative carbohydrate content of the meal calcurated, or using the approximate ratio of 0.08 to 0.12 U/g carbohydrate (slightly more at breakfast)., for ex-ample, prebreakfast (rapid or regular insulin), 15% to 25%; prelunch (rapid or regular insulin), 15 %; predinner (rapid or regular insulin), 15% to 20%. Requirements are increased during intercurrent illness, pregnancy, and the adolescent growth spurt. Of average, insulin doses are increased every 2 to 3 days, and increments can be by as much as 10 % to 20 % of the total daily dose. When blood glucose values rise to more than 13.9 mmol/L, one should check for ketones, which are readily detected in the urine.

Elevations of FPG may be caused by several factors. The Somogyi effect refers to rebound hyperglycemia that follws un-detected hypoglycemia, commonly "nocturnal,'' in the early hours of the morning. The elevated FPG in this situation is treated by decreasing the preceding evening dose of insulin and/or by altering the timing of administration (from predin-net to bedtime) and/or the type of insulin used, based on the expected time to maximal effect of the insulin. This approach causes less hypoglycemia and prevents the redbound. In the dawn phenomenon, the nocturnal secretion of growth hormone is responsible for a nighttime-to-morning rise in blood glucose. This condition is treated by increasing the evening dose of in-sulin and/or by altering the timing of administration and/or the type of insulin used. Poor insulin injection technique is an extremely common reason for increasing insulin requirements or unexplained fluctuations in blood glucose values, despite ad-herence to a strict exercise and nutrition program. Use of dif-ferent anatomic sites for injection may be responsible for vari-able and erratic insulin absorption, and repeated injection into a single site leads to local "resistance"through lipohypertrophy and tissue fibrosis.

Type 2 Diabetes

The aim of treatment of type 2 diabetes is to reverse in-sulin resistance, to control intestinal glucose absorption, to normalize HGP, to improve Q-cell glucose sensing and insulin secretion, and ultimately to prevent the occurrence of long-term complications. Provided pharmacologic therapy is not re-quired immediately, all patients should be given at least a 1-month trial of diet, exercise, and weight management. If this regimen does not lead to adequate blood glucose control, the physician will need to prescribe oral antihyperglycemic agents and/or insulin. Insulin may, in fact, be needed in symptomat-ic patients who have 2diabetes with FPG values exceeding 13.9 mmol/L. After FPG is controlled one may be able to substitute an oral agent. Maximal dose sulfonylurea therapy, with doses decreasing with improved control, has been used ef-fectively as initial treatment in patients presenting with marked hyperglycemia.

The five classes of oral antidiabetic agents currently avail-able are listed in Table 36. The sulfonyluresd and meglitinides have similar mechanisms of action and may cause hypoglycemi-a, hence the term oral hypoglycemic agents. The other classes of oral agents¡¯each target a different pathologic process and are referred to as antihyperglycemic agents. Type 2 diabetes is a progressive disease, and monotherapy is seldom successful in the long term. Combination drug therapy using submaximal doses of two or more agents, including insulin, each targeting a different metabolic abnormality, has synergistic effects that may be far greater than the effects of any agent used alone at maximal dose . The incidence and severity of adverse events are also reduced. Therapy is initiated with one class of agent, depending on the patient's characteristics and the predominant pathogenic defect, and a second agent is added if adequate glycemic control is not achieved at one-fourth to three-fourths maximal dosage. This stepped-care approach is continued until target glucose goals are achieved. Regular blood glucose esti-mations allow timely increases in drug dosage and the addition of other agents as necessary.

Sulfonylureas

The principal action of these drugs is to stimulate endoge-nous insulin secretion from the pancreatic 0 ceils. They also in-crease 0-cell sensitivity to glucose and exert some influence in diminishing insulin resistance. The drugs differ in potency, time of onset, duration of action, plasma protein binding, ab-sorption characteristics, route of metabolism, and excretion. At maximal dose, they are all equally effective (except tolbu-tamide) in lowering blood glucose levels. Primary failure to re-spond to sulfonylureas occurs in 20 % to 25 % of patients. Sec-ondary failure occurs at the rate of 10% to 15% per year, in part because of progressive cell failure and insulin resistance and in part because of poor patient compliance. Replacing one agent with another in this class is unlikely to produce a sub-stantially different effect, and it is not recommended. The risk of hypoglycemia, the major adverse effect, increases with in- creasing patient age, use of a preparation with a long half-life (e. g, chlorpropamide), and renal dysfunction. Weight gain is also a recognized side effect. Characteristics of patients best suited for sulfonylureas include diagnosis at an age over 30 years and disease present for less than 5 years, residual 0-cell function, relative lack of obesity, and FPG less than 16.7 mmol/L.

Biguanides (Metformin)

The major mechanism of action of these insulin sensitizers is in reducing HGP by inhibiting gluconeogenesis. These drugs also increase anerobic glycolysis, enhance glucose uptake and u-tilization by muscle, and decrease intestinal glucose absorp-tion. In addition to their glucose-lowering effect, these drugs are associated with weight loss(5 to 10 lb), possibly related to mild nausea and anorexia, a decrease in plasma insulin levels, and significant lipid-lowering effects (decreasing total choles-terol, LDL, and triglyceride by 10 % to 20 % ). They are well suited for use in obese, hyperlipidemic patients with type 2 di-abetes. Their use in patients with impaired glucose tolerance and the metabolic syndrome as prophylaxis against develop-ment of diabetes is under investigation. Primary failure rates are approximately 12 %, and secondary failure rates are be-tween 5% and 10%.

Major adverse effects are gastrointestinal or metabolic. Gastrointestinal side effects include metallic taste, anorexia, nausea, abdominal discomfort, and diarrhea; these effects are usually mild and transient, and they improve with reduction in dose and administration with meals. The major metabolic side effect is lactic acidosis, which most often occurs in patients with renal disease (creatinine, ¡Ý1.5 mg/dL in men and ¡Ý1.4 mg/dL in women) ,low cardiac output, impaired hepatic func-tion, or excessive alcohol intake.

a-Glucosidase Inhibitors (Acarbose. Miglitol)

Within the small bowel lumen, these agents competitively inhibit the breakdown of complex carbohydrates by antagoniz-ing pancreatic u-amylase and the microvillar brush border a-glucosidase enzymes; thus, they delay glucose absorption and dampen the postprandial glucose and insulin peaks, with mod-est effect on FPG levels. When acarbose is taken with the first bite of a carbohydrate-containing meal, only 1% to 2 % of the drug is absorbed. Major common side effects are gastrointesti-nal, including bloating, abdominal discomfort, diarrhea, and latulence. These effects occur at the initiation of therapy and ay worsen with dose increases, but they commonly disappear with continued use. The side effects can be minimized by starting with an extremely low dose (25 mg or even 12.5 mg once daily) and increasing it gradually over several weeks to a maintenance dose of 50 to 100mg rid depending on the patient's body weight (see Table 36) . These agents do not cause hypoglycemia when they are used alone, but hypo-glycemia occur when they are used in combination with in-sulin, a sulfonylurea, or a meglitinide. Oral treatment of hypo-glycemia during therapy with this agent consists of administer-ing pure glucose, fructose, or lactose( not sucrose, maltose, or starch).

Thiazolidinediediones (Troglitazone, Rosiglita-zone, Pioglitazone)

These agents reduce insulin resistance, improve the pe-ripheral action of insulin,and thereby reduce hyperglycemia by increasing glucose uptake and utilization in peripheral tissues and reducing HGP. Patients have a small improvement in serum lipids (decrease in triglycerides and free fatty acids, in-creased HDL, and increased large "fluffy" LDL). They have little effect in the presence of euglycemia and thus tend not to produce hypoglycemia when used alone. It takes up to 3 to 4 weeks to produce a clinical effect and 10 to 12 weeks for a full effect. Troglitazone' s absorption is enhanced 30% to 85% when the drug is taken with food. Troglitazone has a 25% to 53 % primary failure rate. When these drugs are used in con-junction with insulin therapy, they may facilitate a reduction in insulin dose or even its discontinuation. Troglitazone is cur-rently approved only as an adjunct in patients taking insulin or sulfonylureas with or without metformin. Rosiglitazone may be given as monotherapy or with metformin, whereas pioglita-zone may be used as monotherapy or with insulin, sulfony-lureas, or metformin. A major side effect of troglitazone is liv-er dysfrnction; this appears to be idiosyncratic and, in rare in-stances, has resulted in fatal liver failure. Most cases of liver dysfunction have occurred within the first 6 months of thera-py; generally, hepatic enzyme levels return to normal on dis-continuation of the drug. Serum transam nases need to be monitored frgquently in patients using this class of drugs.

Meglitinides

The only agent currently clinically available in this class is repaglinide. Its mechanism of action is similar to that of the sulfonylureas in stimulating insulin secretion from the pan-creas. The advantages of this class over the sulfonylureas are the rapid onset and short duration of action, which suppress postprandial hyperglycemia. The drug should be taken with meals and is omitted in the absence of a meal, a feature that permits flexibility of lifestyle. The stimulation of prandial in-sulin secretion avoids chronic stimulation of 1; cells and thus leads to less between-meal and nocturnal hyperinsulinemia, which is a feature of sulfonylurea therapy. Repaglinide appears to sensitize cells to secrete more insulin in reponse to a given glucose level, and its insulin secretagogue actionis glucose de-pendent. For this reason, hypoglycemia is seen less often than

with sulfonylureas. Clinical response to this agent is seen in about 1 week. The drug may be prescribed in the presence of renal dysfunction. Combination therapy of a sulfonylurea with repaglinide is not recommended.

Diagnosis in Traditional Chinese Medicine

In traditional Chinese medicine, the disease is categorized as "xiao ke"which means diabetes.

1. The characteristics of a typical case of diabetes mellitus are often polyphagia, polydipsia, polyuria and loss of body weight. Early or asymptomatic patients only show abnormal release of cortical hormone and insulin inside the body. The level of fasting blood sugar is elevated with abnormal glucose tolerance test. Svm0tomatic patients are frequently complicat-ed by other symptoms of dermal, neural and endocrinous disor-ders, besides polyphogia, polydipsia, polyuria and loss of body weight.

2. The main complications and concomitant diseases of di-abetes mellitus are diabetic ketoacidosis, cardiovascular dis-eases, diabetic renopathy and peripheral neuropathy. Cardio- vascular complications are the chief causes of death.

3. Diabetes mellitus is classified into juvenile and adult types according to the clinical features. The age of onset of the juvenile type is young and has a tendency to inheritance. Blood sugar fluctuates widely and is quite sensitive to insulin. Treat-ment is difficult and is easily complicated by ketoacidosis and hypoglycemia, and so it is often named insulin-depending dia-betes or unstable diabetes. The age of onset of adult type is above 40. This type is relatively mild and can be controlled by dietary restriction or oral antidiabetics. Therefore it is also named non-insulin depending diabetes or stable diabetes.

4. Accessory examination :

(1) Fasting blood-glucose is higher than 130 mg. Blood glucose after meal is more than 160-- 180 rag. Urine is posi-tive for glucose. If complicated by ketosis, urine is positive for ketone bodies.

(2)Glucose tolerance test can be used to diagnose early or suspected cases and is the principal test in diagnosis.

(3) New diagnostic techniques such as testing blood in-sulin levels are quite helpful in understanding the pathological changes of pancreas and in obtaining information concerning treatment.

Differentiation and Treatment of Common Syndromes in

Traditional Chinese Medicine

1. Dryness-heat in the lung and Stomach:

Clinical manifestations:Restlessness, polydipsia, polypha-gia with tendency to hunger, dryness of the mouth and tongue, polyuria, red tongue with yellowish fur. slippery and rapid pulse.

Therapeutic method: Nourishing yin and clearing away pathogenic heat.

Recipe: Modified Gypsum Decoction in combination with Nourishing the Stomach Decoction.

Ingredients:

Gypsum Fibrosum 25g

Rhizoma Anemarrbenae 12g

Radix Glehniae 20g

Radix Ophicopogonis 15g

Radix Rehmanniae 20g

Rhizoma Polygonati Odorati 15g

Radix Trichosanthis 30g

Cortex Lycii Radicis 12g

Radix Scrophulariae 12g

Radix Glycyrrhizae 6g

Administration: The above drugs are decocted in an ade-quate amount of water. Take one half of the decoction in the morning and the other half in the evening.

Modification: For the case complicated with constipation.

Radix et Rhizoma Rhei 10g

For the case with ulcerations of the mouth and tongue,

add

Rhizoma Coptidis 10g

Flos Lonicerae 20g

For the case with shortness of breath, fatigue, sponta-neous perspiration and thready weak pulse, add

Radix Codonopsis Pilusulae 10g

Radi Astragali seu Hedysari 15g

Fructus Schisandrae 10g

2. Deficiency of the Kidney-yin :

Clinical manifestations: Polyuria with turbid discharge, soreness and debility of the lumbus, dryness of the mouth and tongue, dysphoria with feverish sensation in the chest, palm and soles, red tongue, deep, thready and rapid pulse.

Therapeutic method: Nourishing yin and supplementing the kidney.

Recipe: Modified Bolus of Six Drugs Including Rehman-nia.

Ingredients:

Radix Rehmanniae 15g

Radix Rehmanniae Praeparata 15g

Rhizoma Dioscoreae 20g

Fructus Corni 10g

Cortex Moutan Radicis 10g

Rhizoma Arisaematis 12g

Poria 10g

Administration: All the above drugs are to be decocted in water to get 200 -- 300ml of decoction. Take equal shares in the morning and in the evening.

Modification: For the treatment of dysphoria with fever-ish sensation in the chest, palms and soles and night sweat,

add

Rhizoma Anemarrhenae 12g

Cortex Phellodendri 10g

for the case indicating impairment of both qi and yin manifested as fatigue, thready and weak pulse, add

Radix Codonopsis Pilosulae 15g

Radix Astragali seu Hedysari 15g

For the case ascribable to the deficiency of yin in the liver and kidney marked by dizziness, blurred vision, and tinnitus,

add

Fructus Lycii 12g

Fructus Ligustri Lucidi 12g

If the course is so prolonged that deficiency of yin affects yang, resulting in deficiency of both yin and yang, manifest-ed as aversion to cold, cold limbs, edema, diarrhea, pale tongue with whitish fur, deep thready and weak pulse, the treatment should be aimed at nourishing the kidney-yin and warming its yang, modified Bolus for Tonifying the kidney-qi is recom-mended for it. The ingredients are: