Authors: Udaya M. Kabadi, MD, FACP, FRCP(C), FACE, Professor of Medicine, Division of Endocrinology, Lucille and Roy Care College of Medicine, University of Iowa, Iowa City, IA; Rameshkumar K. Raman, MD, Division of Endocrinology, Lucille and Roy Care College of Medicine, University of Iowa, Iowa City, IA.
Peer Reviewer: Serge Jabbour, MD, Associate Professor of Medicine, Division of Endocrinology, Thomas Jefferson Hospital, Philadelphia, PA.
Normal circulating plasma glucose concentration is maintained by a delicate constant balance between glucose utilization (i.e., glycolysis or storage as glycogen by various tissues) on one hand and glucose production on the other (i.e., glycogenolysis and gluconeogenesis induced in certain tissues, such as liver, muscle, renal parenchyma, and adipose tissue). During the late post-absorptive period or starvation, normal glucose concentration is maintained by facilitating glucose production while inhibiting glucose uptake. In contrast, during the immediate post-absorptive period, glucose is provided by conversion of dietary nutrients, i.e., complex carbohydrates as well as proteins and fats, with minor contribution by the hepatic glucose production.
Glucose is the major and most efficient fuel for maintenance of normal function by all cells in the body, and insulin is required for glucose entry and utilization in all these cells, with the only exceptions being the nervous system, the renal medulla, and erythrocytes. Alternatively, glucose production is promoted by counter-regulatory hormones, i.e,. glucagon, catecholamines, glucocorticoids, and human growth hormone in concert with declining insulin concentration.1 Thus, in principle, the basic pathophysiology in development of hyperglycemia in diabetes involves increased glucose production and decreased glucose uptake by the tissues. In Type 1 diabetes mellitus, hyperglycemia results from lack of insulin secondary to destruction of pancreatic beta cells, while insulin resistance in concert with an altered insulin secretory pattern leads to hyperglycemia in Type 2 diabetes mellitus.2
Appropriate management of hyperglycemia in Type 1 diabetes requires exogenous insulin administration with attainment of a normal or near normal daily insulin secretary pattern in conformity with daily routine schedule of meals and activities. In Type 2 diabetes, the ideal therapy may include both the amelioration of the insulin resistance and improvement in insulin secretory pattern. Therefore, the knowledge of insulin pharmacokinetics is essential in physiologic management of hyperglycemia in both Type 1 and Type 2 diabetes mellitus.
Pharmacokinetics is distinctly different for endogenously secreted insulin in comparison to exogenously administered insulin.3 Normally, insulin is secreted by pancreatic beta cells directly into portal circulation and, therefore, is promptly utilized, cleared, and degraded by the liver (50%). The remaining amount then enters the systemic circulation and is utilized by other tissues (muscle, renal parenchyma, etc.) and therefore a little is excreted by the kidneys. The fate of exogenously administered insulin follows a distinctly different pattern. Initially, it enters the peripheral venous circulation and then is transported to all the tissues, including the liver and kidneys, via systemic arterial circulation. Therefore, the clearance of exogenously administered insulin occurs primarily by the kidneys. The exact pharmacokinetics of exogenously administered insulin also is influenced by several factors, including the type of insulin (See Table 1), the routes of administration (See Table 2), dose and site of administration, the rate of absorption, and the integrity of systemic circulation.4 The circulating half-life following intravenous administration is extremely short (5-10 minutes) in comparison to other routes, although it is similar for both regular insulin and glargine insulin.5 The larger the dose, the longer the half-life is, in conformity with exogenous administration of other drugs. However, the initiation, peak, and duration of action of insulin analogs also vary widely on subcutaneous administration. (See Table 1.)
Several factors influence the absorption of insulin following subcutaneous administration.6,7 The rate of insulin absorption is inversely proportional to the concentration and volume of injected insulin. Insulin absorption is enhanced by a relatively increased subcutaneous blood flow (i.e., from exercise, massage, heat, etc.) or dilute insulin solution. In contrast, factors inducing decreased insulin absorption include compromised subcutaneous blood flow (i.e., from cold, shock, or standing), lipohypertrophy or atrophy at the site of subcutaneous administration, or occasionally local destruction by an antibody.8 The absorption also is altered if insulin is administered via an erroneous route directly into the capillary or by the intramuscular instead of subcutaneous route. Finally, the rate of absorption varies with the site of administration for all insulins with the exception of insulin glargine.
The most rapid absorption occurs following subcutaneous administration into the abdominal wall, whereas the absorption is slowest for subcutaneous administration into the thighs, with subcutaneous administration into the arms leading to an intermediate rate.9 In contrast, the rate of absorption of insulin glargine is almost identical irrespective of the site of subcutaneous administration.10 Although the subcutaneous route is used most commonly, other routes are used in special circumstances. Intravenous insulin infusion is a preferred route in sick subjects during hospitalizations for diabetic ketoacidosis, hyperglycemic hyperosmolar state, or other acute illnesses (i.e., MI, stroke, sepsis, etc.) as well as during perioperative or perinatal periods.11,12 Intraperitoneal administration has been used in subjects undergoing intermittent peritoneal dialysis or in a rare occurrence of destruction of insulin at the site of administration into subcutaneous tissue.13-15 Alternatively, the intramuscular route has been used occasionally.15
Principles of Insulin Therapy
Desirable glycemic control [HbA1c < 7.0%] is shown to reduce, delay, or prevent the onset or progress of complications, as seen in the Diabetes Control Complications Trial (DCCT) as well in other studies.16-21 The daily glycemic goals to achieve desirable HbA1c concentration consist of pre-meal blood sugar between 80-120 mg/dL and 2 hours post-meal blood glucose concentration of less than 140 mg/dL. The most effective tactic to achieve desirable diurnal glycemia in Type 1 diabetes mellitus is to mimic the normal insulin secretory pattern consisting of a constant basal insulin level without a peak between meals, with its longest duration between bedtime and breakfast the next day, and a bolus insulin expressed as a prompt rise within 15-30 minutes following each meal.
Therefore, what until recently was called intensive therapy now has become a standard of care. This strategy demands careful attention to lifestyle modifications used concurrently with attainment of a normal diurnal insulin pattern. Therefore, frequent adjustments of insulin dosage based on pre-meal and postmeal blood glucose concentrations may be required to meet the changing circumstances. Two approaches in this regard include: 1) multiple daily injections (MDI) of rapidly acting insulin administered as boluses prior to meals, with administration of either a single or a split dose of intermediate- or long-acting insulin to mimic the basal pattern; or 2) a continuous subcutaneous insulin (CSII) administration along with pre-meal boluses of short-acting insulin.16,19,22,23
Ideal basal insulin should closely mimic normal pancreatic basal insulin secretion between meals with no distinct peak. The insulins used to achieve a basal effect until recently have been ultralente, lente, and NPH insulins. However, they fall short of achieving a basal pattern because of their profiles and, therefore, pose many disadvantages, including:
- Induction of a peak after administration that tends to cause an increase in the risk of nocturnal, fasting, and frequently daytime hypoglycemia;
- Variability in day-to-day profiles because of changing absorption following subcutaneous injection due to insoluble suspension in formulation;
- Less uniformity of peak levels depending on variability of absorption from various sites of administration;8,9 and
- Because of the intermediate (18-24 hours) duration of action with lente or NPH insulins and even a longer duration with ultralente insulin, a single dose rarely is adequate to achieve consistent diurnal basal concentrations.
In contrast, insulin glargine tends to achieve a consistent level without a peak, close to a normal basal pattern lasting about 24 hours, with once-daily administration in most subjects.24 However, attaining and maintaining a stable basal pattern is not adequate to control postprandial glycemia.
In normal individuals, plasma insulin levels peak within 30-60 minutes following meals and blunt early postprandial glycemic excursions. (See Figure 1.) In subjects with Type 1 diabetes mellitus, attempts therefore are made to mimic the postprandial insulin pattern by administering rapid-acting insulins (see Table 1) immediately prior to meals or occasionally immediately post-mealespecially in subjects with delayed gastric emptying due to gastroparesis as well as those with erratic eating patterns. Slower absorption from subcutaneous depots may result in a delay of the physiologic peak level after meals, with the induction of immediate postprandial (1-2 hours) hyperglycemia. Delayed absorption also may lead to inappropriately high levels of insulin between meals, leading to late postprandial (3-4 hours) hypoglycemia. Fortunately, the newer rapid-acting insulin analogs lispro, aspart, or glulisin appear to mimic more closely the kinetics of a postprandial physiologic endogenous insulin pattern and, therefore, in conjunction with insulin glargine, help achieve the overall daily physiologic insulin profile closer to the one noted in normal subjects.
Adults with Type 1 diabetes manifest only minimal or no insulin secretion. Therefore, their initial daily insulin requirements of 0.5-0.6 units per kilogram of body weight tend to be similar to an average daily insulin production in normal adults. The daily insulin requirement includes both the basal and the prandial needs. The basal requirement is approximately 40-60% of the total daily dose to maintain normal fasting as well as pre-prandial glycemia via inhibition of hepatic glucose output. The remainder of the daily dose is for pre-meal administration as rapid-acting insulin to blunt postprandial hyperglycemia. Subjects requiring fewer than 0.5 units per kilogram of body weight frequently demonstrate the presence of some endogenous insulin production. Alternatively, the lesser requirement at the initiation of insulin therapy in Type 1 diabetes mellitus may be due to increased insulin sensitivity because of the up-regulation of insulin receptors in the absence of insulin. Finally, the simultaneous presence of other disorders may lead to a reduced daily insulin requirement in subjects with both Type 1 and Type 2 diabetes mellitus. These other disorders include renal failure inducing decreased insulin clearance, a lack of the counter-regulatory hormones cortisol, thyroid hormones, and human growth hormone in the presence of adrenocortical insufficiency and hypothyroidism or hypopituitarism, respectively, and lack of catecholamines or inhibition of their effects in presence of autonomic dysfunction. The daily insulin requirement in children usually amounts to 0.1-0.2 units per kilogram of body weight and gradually rises to almost 1.0 unit per kilogram of body weight during adolescence before decreasing to adult levels, with the highest daily dose in adolescents being attributed to spurts of human growth hormone.
Basal insulin production also varies throughout the day because of the diurnal rhythm of counter-regulatory hormones (growth hormone and cortisol) as well as rises and falls in circulating catecholamine concentrations secondary to physical and emotional lability. This diurnal basal insulin pattern has become evident in subjects with Type 1 diabetes mellitus using an artificial endocrine pancreas (Biostator, closed loop system) and continuous subcutaneous insulin infusion or insulin pumps (CSII). The basal insulin requirement of most subjects remains constant from 8 a.m. to midnight, with a decrease of almost 50% from midnight to 4 a.m., followed by an increase by about 50% from 4 a.m. to 8 a.m. once again attributable to a diurnal pattern of counter-regulatory hormones.25-29
Various insulin delivery methods for subcutaneous administration have evolved since the discovery of insulin. (See Table 3.) Historically, regular, or crystalline, insulin was the only formulation available and was administered subcutaneously pre-meal several times per day. Soon, the focus of therapy became convenience, and intermediate- or long-acting insulins were developed in an attempt to reduce daily multiple injections to one daily morning injection. The pitfalls of one daily injection in achieving control of glycemia were recognized with the advent of improved methods of assessment of diurnal glycemia, including home blood glucose monitoring. Therefore this regimen gave way to twice-daily injections of combinations of intermediate-acting and short-acting insulins, i.e., intensive conventional therapy of the 1970s. Although this regimen did improve glycemic control over the single dose regimen, the introduction of methodologies in assessment of long-term glycemic control over three months (i.e., HbA1c) or intermediate glycemic control over 2-3 weeks, with determination of fructosamine, and with further refinement in technological devices for capillary blood glucose determination, it became apparent that desirable glycemic control could not be attained or maintained with this intensive conventional therapy. With further advances in diabetes research, it also became apparent that pancreatic or islet cell transplantation or use of an artificial pancreas with computerized adjustment of the insulin infusion rate based on glucose readings obtained by a glucose sensor are the most effective methods in achieving near normal glycemia.30,31 However, the transplantation of pancreas or islet cells has its own disadvantages, including the consequences of long-term immunosuppressive therapy and its side effects, the life span of the transplants themselves, and the need for recurrent transplants. Moreover, a portable closed loop system is yet to be developed.
With the use of a an artificial endocrine pancreas, the normal insulin secretory pattern in terms of basal and post-meal bursts was firmly established and the need for mimicking the normal physiologic insulin secretion to attain and maintain diurnal near normal glycemia was recognized, leading to the introduction of multiple (greater than 2) daily subcutaneous injections of basal and pre-meal short-acting insulins, i.e., true intensive therapy.
Finally, for achieving greater convenience over multiple injections, yet another method of optimal insulin delivery was developed in the form of continuous subcutaneous insulin infusion (insulin pump). However, present insulin pumps are open loop systems lacking glucose sensors and therefore need very close monitoring by an intelligent, mature, and committed patient who may need to perform capillary glucose testing several times per day, especially to avoid prolonged hyperglycemia or hypoglycemia. Hypoglycemia may be especially dreadful because it could remain sustained due to the pump's inability to discontinue or reduce the rate of insulin infusion, resulting in convulsion, coma, and occasionally death. In some patients, diabetic ketoacidosis occurs because of a lack of adequate frequency of blood glucose monitoring and declining appropriate assessment of equipment. This may occur from over-confidence and a lackadaisical attitude on the part of patients, as well as their hesitancy to use subcutaneous insulin injections as instructed even in the presence of worsening hyperglycemia. Therefore, the insulin pumps need to be examined by personnel with the knowledge and experience of proper equipment functioning at least at a yearly interval. Moreover, it is important to monitor the patient's ability to maintain adequate technical performance. Therefore, insulin pumps must be reserved only for certain groups of patients, mainly those with Type 1 diabetes mellitus who are intent on continuing education and preparedness to perform frequent diurnal blood glucose monitoring and use subcutaneous insulin if needed in certain circumstances. Unfortunately, many patients do not belong to this category and, therefore, the brunt of insulin therapy revolves around a regimen consisting of multiple daily insulin injections (MDI) consisting of a combination of basal and rapid-acting insulins. In actuality, several studies have demonstrated comparable efficacy of both MDI and CSII in achieving desirable glycemic goals.32-34 Recently, NPH, lente, and ultralente insulins have given way to insulin glargine because of its profile in achieving a consistent physiologic basal insulin pattern. Therefore, subcutaneous administration of insulin glargine once or twice daily along with pre-meal rapid-acting bolus insulin appear to provide the most physiologic circulating insulin pattern throughout the day in most ambulatory patients consuming regular meals.
Initiation of Insulin Therapy in Type 1 Diabetes Mellitus
Conventional Regimen. Initially, a total daily dose is established as 0.4 units/kg of body weight and divided into two-thirds of intermediate and one-third of short-acting insulin, respectively. The dose of intermediate- and rapid-acting insulins is divided into two-thirds prior to breakfast and one-third prior to dinner. Individual doses then are adjusted based on blood sugar readings determined prior to meals or two hours after meals to attain the desirable levels of glycemia. Unfortunately, the adjustment of individual types in premixed forms, i.e., 70N/30 R, 75N/25 lispro, or 70 N/30 aspart, is not feasible. Therefore, this regimen in most patients, although simple, convenient, and acceptable, is unable to achieve desirable long-term glycemic control (HbA1C less than 7%) without frequent hypoglycemic episodes, especially during the night because of the peaks following the evening administration of intermediate-acting insulin.35
Another modification of this regimen involves use of intermediate-acting insulin at breakfast and bedtime with rapid-acting insulin prior to breakfast and dinner. This regimen may lower the incidence of nocturnal hypoglycemia and suppress the rise of blood glucose at dawn. However, in most patients this method also fails to attain and maintain a desirable glycemic target without significant reduction in episodes of hypoglycemia.36 A small population of patients may be able to achieve adequate glycemic control as recommended by the American Diabetes Association (ADA) with one of these regimens and, therefore, could continue the same.
Intensive Conventional Regimen. This method intends to mimic the normal physiologic secretory pattern, consisting of several combinations of rapid-acting and intermediate- or long-acting insulins. One of these involves the administration of intermediate-acting insulin (NPH/lente) at bedtime with rapid-acting insulin lispro, aspart, or glulisin insulin prior to meals. Short-acting regular insulin may be used instead of the rapid-acting insulins because of its slightly longer duration of action anticipated to compensate for the lack of use of intermediate insulin during daytime, especially in the presence of gastroparesis. Another approach used for the intensive conventional regimen is the administration of long-acting insulin (ultralente) once or twice daily prior to breakfast and dinner mixed with either a short- or rapid-acting insulin, and yet another injection of short- or rapid-acting insulin prior to lunch. Another intensive regimen recently described consists of administering several injections (about 4), with mixtures of various insulins.
Finally, all these regimens require adjustments of short- or rapid-acting insulin dosages prior to meals based on the capillary blood glucose readings obtained prior to or at two hours after meals, i.e., supplemental or correction regimens. (See Table 4.) Although all these intensive regimens were able to attain and maintain desirable glycemic control (HbA1c less than 7%), the prevalence of hypoglycemia was three times greater in comparison to the conventional regimen,16 a distinct obstacle in formula-ting a safe, effective, and viable option. The increased prevalence of hypoglycemia with these regimens was attributed to the peaks achieved by any of the insulins (ultralente, NPH, lente) used to mimic a normal basal pattern.
These drawbacks were a major impetus for research leading to the synthesis of an ideal basal, peakless insulin glargine, which in combination with pre-meal rapid-acting insulin mimics normal physiologic insulin secretion. (See Figures 1 and 2.) Moreover, insulin glargine, because of several unique characteristics (see Table 5), opened a new era in research and development of other insulin analogs with similar properties. Several studies have established the efficacy of insulin glargine in achieving greater uniformity of glycemic control in comparison to NPH, lente, or ultralente insulin when used concurrently with the administration of rapid-acting insulin prior to meals, with a significant lowering of both the episodes of nocturnal hypoglycemia and rising rebound daytime glycemia.37,38 Moreover, the dose of insulin glargine could be titrated to attain near normal morning fasting glycemia (90-130 mg/dL) because of fewer occurrences of nocturnal hypoglycemia, leading to the need for less rapid-acting insulin prior to meals with further decreased events of hypoglycemia during the daytime as well. Thus, overall use of insulin glargine instead of older intermediate-acting insulins for mimicking a normal basal pattern may attain and maintain HbA1c less than or equal to 7% as recommended by the ADA and even less than 6.5% as recommended recently by other organizations such as the American Association of Clinical Endocrinologists (AACE) and the International Diabetes Federation (IDF) without increasing significantly the risk of hypoglycemia. Finally, although the use of insulin glargine initially was approved for use at bedtime, newer studies have demonstrated that it could be administered at any time during the day without loss of efficacy or greater risks of hypoglycemia as long as the time of administration remains the same every day.39
|Table 5. Properties of Glargine Insulin|
This regimen may be more cost-effective than the older intensive regimens of the past. Cost savings may be realized because of reduction in nocturnal hypoglycemic events40 due to its peakless profile, and during the day because of the decreased pre-meal dosage of rapid-acting insulin secondary to efficacy of glargine in achieving lower fasting blood sugar. Moreover, there is no need for a bedtime snack with blood sugars greater than or equal to 150 mg/dL because of reduced nocturnal hypoglycemia, and the better long-term glycemic control achievable by insulin glargine also may help lower both short-term and long-term costs. (See Table 6.) Finally, initiation of this regimen is simple and practical and can be achieved in all patients with Type 1 diabetes mellitus (see Table 7), including children and adolescents. However, mixing glargine (with acidic pH) with other insulins or normal saline that have neutral pH is not currently recommended because of a concern regarding alteration of their individual activity and efficacy. Therefore, glargine must not be mixed either in the syringe and or even at the site of subcutaneous administration. However, this recommendation may be more precautionary and presumptuous rather than factual, as noted in a recent report.41
|Table 6. Initiation of Glargine Insulin in Type 1 DM|
|Table 7. Probable Cost Advantages for Regimens Using Insulin Glargine|
Insulin Therapy in Type 2 Diabetes
The benefits of attaining and maintaining desirable glycemic control in lowering morbidity, mortality, and cost have been well-established.16,17,19-21 Therefore, aggressive management of Type 2 diabetes with lifestyle modifications, oral hypoglycemic agents, and insulin to achieve recommended goals must become a standard medical practice. Moreover, in subjects with Type 2 diabetes, it is relatively easier to achieve more uniform glycemic control than in Type 1 diabetes, due to the influence of persistent, endogenous insulin secretion even during the late stage of disease.42 Finally, subjects with Type 2 diabetes mellitus demonstrate better counter-regulatory mechanisms to combat hypoglycemia until the advanced stage of disease.43 However, insulin therapy frequently is withheld or delayed in Type 2 diabetes mellitus because of the fear of hypoglycemia on the part of both the provider and the patient, and the fear of injection on the part of the patient. Another reason for withholding or delaying administration of insulin is the erroneous impression on the part of the provider that insulin is atherogenic in nature. This is a misconception and misrepresentation derived from epidemiological studies showing a relationship between hyperinsulinemia and cardiovascular outcomes.45-47 One must realize that the adverse cardiovascular outcomes are secondary to insulin resistance, and hyperinsulinemia was a simple, calculable, mathematical surrogate marker of insulin resistance. In fact, several studies have shown that HbA1c levels are closely related to cardiovascular outcomes as well as other complications in Type 2 diabetes mellitus, and that intensive insulin therapy by achieving desirable glycemic control may delay the onset or retard the progress of these complications.47-50 Recent studies have demonstrated improvement in outcomes with insulin therapy, lowering glycemic levels even in sick non-diabetic subjects via amelioration of inflammation, improvement in endothelial function, and enhancement of immune mechanism.51-54 Therefore, the initiation of insulin in Type 2 diabetes must not be delayed or withheld in appropriate situations (see Table 8), since the lack of insulin use frequently leads to worsening manifestations with a delay in recovery and prolonged hospitalization.
Historically, in ambulatory subjects with a lapse of glycemic control while receiving oral agents, administration of NPH insulin at bedtime, 70/30, N/R insulin prior to supper, or ultra-lente insulin prior to breakfast were used in combination with oral agents (i.e., sulfonylurea) to provide basal insulin during the night to blunt nocturnal hepatic glucose production and lower fasting glycemia.55-59 Simultaneously, these insulins also achieve early or late nocturnal peak, inhibit release of endogenous insulin, and therefore enhance insulin stores in beta cells. Administration of sulfonylurea enhances release of this stored insulin following a meal and blunts post-prandial glycemia during the daytime. Sulfonylureas, especially glimepiride, also may improve sensitivity of tissues to exogenous insulin and lower glycemia by enhancing glucose uptake.60-62 Alternatively, insulin sensitizers (i.e., metformin and glitazone) blunt diurnal glycemia by enhancing insulin sensitivity in the peripheral tissues to exogenous insulin. Therefore it was anticipated that use of insulin sensitizers may lower the daily insulin dose more than sulfonylurea. However, exactly the opposite finding was noted in studies, which demonstrated greater lowering of the daily insulin dose by sulfonylurea in comparison to either metformin or the presently approved glitazones.63-65 Also, using a combination of sulfonylurea with metformin appears to lower the daily insulin dose maximally, with a greater reduction in hypoglycemic events as well as weight gain.66 Other benefits may be gained by such a combination therapy with insulin in comparison to insulin monotherapy. One injection of insulin frequently used in a combination regimen in contrast to multiple injections required with insulin monotherapy to achieve reasonable glycemic control distinctly provides a greater convenience and therefore renders better compliance, especially in the elderly. Furthermore, the smaller amount of weight gain noted with the combination therapy in comparison to insulin monotherapy may be beneficial in preventing or delaying consequences of weight gain, particularly worsening insulin resistance with increasing daily insulin dose and worsening lipid profile.67 Finally, combination therapy consisting of insulin and sulphonylurea also has been shown to be more cost-effective in comparison to insulin monotherapy.68
With all of these different regimens, however, using older intermediate- or long-acting insulins to attain and maintain HbA1C less than or equal to 7.0% was difficult because of a significant prevalence of nocturnal hypoglycemia necessitating a decrease of the insulin dose. Recent studies using insulin glargine with a more physiological basal profile have demonstrated that a significantly greater number of subjects using insulin glargine at bedtime attained HbA1C less than or equal to 7.0% with fewer hypoglycemic events in comparison to administration of NPH insulin at the same time.69,70 Furthermore, insulin glargine may be administered at any time of the day (i.e., before breakfast, before lunch, or before dinner, or at bedtime) as long as the time remains the same every day without a lapse of glycemic control based on recent studies.39,83 Thus basal insulin therapy may be initiated appropriately with insulin glargine in subjects with Type 2 diabetes mellitus who have lapsed adequate glycemic control on oral agents with adherence rate of more than 90%. (See Table 9.) However, a combination of oral agents with basal insulin must include a sulfonylurea, preferably glimepiride, because of its efficacy in facilitating both phases of postprandial insulin secretion to successfully ameliorate postprandial hyperglycemia.84 (See Figure 3.) In the absence of sulfonylurea, sensitizers, especially glitazones, fail to improve postprandial insulin secretion necessitating preprandial administration of rapid-acting insulin.85-87 The addition of rapid-acting insulin may not be necessary in some subjects with well-preserved endogenous insulin stores and production. However, rapid-acting insulin may be used prior to meals if HbA1c remains greater than 6.5% despite achieving desirable fasting glycemia (80-120 mg/dL), suggesting persistent postprandial hyperglycemia confirmed by blood sugar readings.
Insulin in Diabetics Under Special Circumstances
Renal Failure. In patients with advanced nephropathy (creatinine clearance less than 20 mL/minute), the insulin requirement may be reduced by as much as 50%. Sometimes, patients with Type 2 diabetes mellitus who progress to advanced nephropathy discontinue insulin therapy as their residual insulin production in the presence of renal failure is sufficient to achieve desirable glycemic control. Institution of dialysis often leads to an increase in insulin requirement on the day of dialysis because of increased clearance, while remaining the same on days between dialysis sessions. In patients being managed with intermittent peritoneal dialysis, insulin can be administered intraperitoneally in a substantially larger dosage in comparison to the subcutaneous requirement.13-15
Pregnancy. Insulin is the only available modality of therapy even in Type 2 diabetes mellitus since oral agents are not approved for use in pregnancy.71 The insulin analogs presently approved for usage during pregnancy are NPH, regular, and lispro insulin. Safety for other insulins, including glargine, has not been established. It may be a safe and efficacious option as described in an isolated case report;72 however, routine use of insulin glargine must await further assessment. Insulin requirements may fall slightly during the first trimester, gradually followed by a rise in the second trimester, and reaching a peak in the third trimester. Immediately after delivery, however, the requirements decline precipitously and return to the pre-pregnancy dosage.73-75 These patients need intense glycemic control and frequently need multiple daily injections of insulin or continuous subcutaneous insulin infusion along with close monitoring of blood sugars pre- and post-meals, at bedtime, and occasionally at 2 a.m.
Old Age. Adjustment of the insulin regimen at regular follow-up visits is essential because of declining renal function and a special need to avoid hypoglycemia, which could result in morbidity (i.e., stroke, MI, or occasionally even death). Administration of premixed insulin preparations may be adequate because of lack of need for intensive control and a greater need for prevention of hypoglycemia, therefore making it a convenient option and rendering better compliance.76 In subjects with Type 2 diabetes mellitus, one injection of basal insulin in combination with oral agents often is adequate to attain a desirable glycemic goal with little risk of hypoglycemia. This therapy is more convenient and therefore results in better compliance in comparison to insulin monotherapy, frequently requiring multiple injections.
Children and Adolescents. Insulin was the only approved modality of treatment in this age group until recent approval of metformin for patients older than 10 years. Moreover, ongoing trials with other oral agents based on pathophysiology of the disorder offer a promise for treatment of Type 2 diabetes mellitus in these age groups. However, for present, insulin remains the only viable option in children younger than 10 years of age.
Surgery. General anesthesia requires special precautions. The metabolic aim in a surgical patient is to avoid hypoglycemia and to prevent blood sugar excursions over 180 mg/dL. Elective surgery should be performed only after attaining desirable glycemic control. Generally, patients should receive the usual dose of insulin glargine on the day prior to surgery. Alternatively, in patients using older intermediate- or long-acting insulins (ultralente), 50% of the daily dose may be administered subcutaneously on the morning of surgery, with a reduction in the previous evening dose by 20%. During the day of surgery, an infusion of 5% dextrose at 100 mL per hour is advisable until resumption of oral intake, with subcutaneous administration of rapid-acting insulin every 3-4 hours to maintain blood sugar between 120-180 mg/dL. A more physiologic and effective option is IV insulin infusion at rate of 0.5-2 units per hour with hourly adjustment of the rate based on blood sugar readings, especially during procedures such as cardio-pulmonary bypass because of changing insulin requirements during hypothermia and re-warming stages. Finally, the pre-operative regimen should be resumed with initiation of oral intake.77,78
Diabetic Gastroparesis. Pre-meal administration of a short-acting insulin over a rapid-acting insulin may be more physiologic in these patients because of the delay in digestion and absorption of food causing erratic postprandial glucose levels. Alternatively, rapid-acting insulin also could be administered immediately after a meal with adjustment of the dose depending on the amount of intake.
Diabetic Ketoacidosis or Hyperosmolar Nonketotic Coma. Intravenous regular insulin administration is the most appropriate therapeutic option.79 Initial bolus based on body weight and degree of hyperglycemia (0.1 unit/kg with blood sugar between 200-500 mg/dL, 0.15 units/kg with blood sugar between 500-1,000 mg/dL, and 0.2 unit/kg with blood sugar greater than 1000 mg/dL) is administered followed by a continuous IV infusion at a rate of 0.1 unit/kg/hour with re-administration of a bolus as well as adjustment of infusion rate to achieve a 10% fall in blood glucose at hourly intervals. The important contributions to therapy include a frequent and close follow-up assessment for adequate insulinization and maintenance of fluid and electrolyte balance.
For further details, readers are referred to ADA practice guidelines for 2004.80
Insulin Use in Subjects Without Diabetes Mellitus
Insulin had not been used in non-diabetic subjects because of fear of hypoglycemia. Initial use of insulin in subjects without diabetes was conducted in the NIH-sponsored Diabetes Prevention Protocol.81 In this study, insulin was administered daily or intermittently to the pro-bands of subjects with Type 1 diabetes mellitus prior to onset of hyperglycemia or ketonemia during a pre-diabetes state in the presence of islet cell antibodies and a decline in first phase insulin secretion following IV glucose administration. The study was terminated because no significant benefit was noted in prevention of Type 1 diabetes mellitus. The authors have demonstrated effective use of insulin in reversing the catabolic state into anabolic process in subjects with AIDS.82 In these studies, with improvement in nutritional status, several laboratory parameters normalized, and enhancement of immune mechanisms were noted. Similarly, intravenous insulin infusion lowered stress hyperglycemic levels of 160-200 mg/dL to 110-120 mg/dL and improved outcomes in critically ill subjects.51 None of these studies documented significant symptomatic or asymptomatic hypoglycemia, allaying concerns about administration of insulin in non-diabetic subjects.
Side Effects of Insulin Therapy
The side effects of insulin therapy include the following:
Hypoglycemia. Fortunately, occurrence of hypoglycemia has declined over the years with the advent of newer insulins and better understanding of insulin pharmacokinetics.
Post-hypoglycemic Hyperglycemia (Somogyi Phenomenon). This has declined as well because of reduction in number of hypoglycemic events.
Lipoatrophy or Lipohypertrophy. Lipoatrophy is immune-mediated and less frequent now with the use of purified synthetic insulins.
Insulin Allergy. The occurrence of this side effect is greatly reduced with the use of purified forms of animal insulins and even more with the use of insulins synthesized by recombinant DNA technology.
Edema. This is a rare phenomenon due to the sodium-retaining effect of insulin on the kidney, with a minor contribution by declining natriuresis secondary to decreasing glucagon concentrations.
Attainment and maintenance of near normal diurnal glycemia with achieving HbA1c less than or equal to 7.0% or less than or equal to 6.5% in subjects with both Type 1 and Type 2 diabetes mellitus has been recommended by many organizations. However, the glycemic target must be individualized. In the young and middle-aged population, this goal is acceptable because of the persistence of hypoglycemia awareness and their ability to combat hypoglycemia without outside assistance. In contrast, the glycemic goal may be raised to avoid hypoglycemia as much as possible in the elderly or in patients with cardiovascular disease or hypoglycemia unawareness, since a hypoglycemic event could be prolonged and may induce a significant morbidity, i.e. stroke, myocardial infarction, and even mortality. Therefore, the appropriate glycemic target in an individual subject must be the lowest HbA1c achievable with minimal hypoglycemia in the presence of awareness or none at all, especially in the elderly.
Insulin administration is the only therapeutic option in subjects with Type 1 diabetes mellitus and is needed for survival. The best approach of insulin therapy in Type 1 diabetes mellitus involves provision of exogenous insulin analogs to mimic the normal endogenous insulin secretory pattern consisting of basal insulin between meals and prompt insulin bursts following meals. Historically, the attainment of this pattern has been difficult and unrealistic because none of the intermediate- or long-acting insulins provide basal peakless profiles. Moreover, the peaks often are erratic and cause significant occurrence of hypoglycemic events, especially during the night, thus preventing attainment of near normal glycemia and a desirable HbA1c level. With the advent of insulin glargine, via its more physiologic basal property, a more uniform diurnal glycemic control with a decline in hypoglycemic events has become feasible. Presently, one injection of insulin glargine and pre-meal administration of rapid-acting insulin has been shown to achieve comparable glycemic outcomes attained by continuous subcutaneous insulin infusion, also described as insulin pump. Therefore, this insulin regimen may be preferred over older regimens in Type 1 diabetes mellitus.
Insulin therapy also is distinctly indicated in subjects with Type 2 diabetes mellitus. Insulin administration frequently is initiated in subjects lacking glycemic control while receiving oral agents in their maximum daily dose. This approach is equally or even more effective than insulin monotherapy and provides several other benefits, i.e., fewer hypoglycemic events, less weight gain, lower cost with a greater convenience, and, therefore, a better compliance. However, during pregnancy and in children younger than 10 years even with Type 2 diabetes mellitus, the only approved therapy by Food and Drug Administration is insulin. Finally, insulin therapy must not be withheld in patients with Type 2 diabetes mellitus in the presence of stressful circumstances or severe symptomatic hyperglycemia and ketoacidosis, both requiring prompt resolution.
Recently, insulin therapy is being extended to subjects without diabetes mellitus in certain stressful circumstances with improvement in outcomes. Therefore, administration of newer insulin analogs in appropriate doses and at appropriate times during the day have significantly lowered the prevalence of adverse effects, including severe hypoglycemia, rendering this therapy safe and effective in both types of diabetes mellitus as well as in the non-diabetic population during certain situations.
Appendix: In September, an FDA advisory panel recommended approval of an inhaled insulin preparation. The inhaled insulin may be used as a substitute in place of preprandial rapid-acting insulin. It can achieve appropriate serum levels like other subcutaneous rapid-acting insulins but in markedly higher dosage. It may cause a minor reduction in pulmonary function in the long term, and absorption may be affected by acute or chronic lung or respiratory disease and probably smoking.
1. Riza RA, Cryer PE, Gerich JE. Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation. Effects of somatostatin and combined alpha- and beta-adrenergic blockade on plasma glucose recovery and glucose flux rates after insulin-induced hypoglycemia. J Clin Invest 1979;64:62-71.
2. Brunzell JD, Robertson RP, Lerner RL,et al. Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J Clin Endocrinol Metab 1976;42:222-229.
3. Rosenzweig JL. Joslin's DM, 13 th Ed: Lea and Febiger 1994:460.
4. Heinemann L, Richter B. Clinical pharmacology of human insulin. Diabetes Care 1993;16 Suppl 3:90-100.
5. Mudaliar S, Mohideen P, Deutsch R, et al. Intravenous glargine and regular insulin have similar effects on endogenous glucose output and peripheral activation/deactivation kinetic profiles. Diabetes Care 2002;25:1597-1602.
6. Koivisto VA, Felig P. Effects of leg exercise on insulin absorption in diabetic patients. N Engl J Med 1978;298:79-83.
7. Linde B. Dissociation of insulin absorption and blood flow during massage of a subcutaneous injection site. Diabetes Care 1986;9:570-574.
8. Binder C, Lauritzen T, Faber O, et al. Insulin pharmacokinetics. Diabetes Care 1984;7:188-199.
9. Koivisto VA, Felig P. Alterations in insulin absorption and in blood glucose control associated with varying insulin injection sites in diabetic patients. Ann Intern Med 1980; 92:59-61.
10. Owens D, Luzio S, Beck P, et al. Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites. Diabetes Care 2000;23:813-819.
11. ADA Position Statement. Hyperglycemic Crises in Patients with Diabetes Mellitus. Diabetes Care 2003;26:S109-117.
12. Umpierrez GE, Khajari M, Kitabchi AE. Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Nonketotic Syndrome. Am J Med Sci 1996;311:225.
13. Scavini M, Pincelli A, Petrella G, et al. Intraperitoneal insulin absorption after long-term intraperitoneal insulin therapy. Diabetes Care 1995;18:56-59.
14. Tzamaloukas AH, Oreopoulos DG. Subcutaneous versus intraperitoneal insulin in the management of diabetics on CAPD: A review. In: Khanna, R, Nolph, KD, Prowant, B, et al, eds. Adv Peritoneal Dial, Vol 7. Toronto: University of Toronto Press; 1991:81-85.
15. Micossi P, Cristallo M, Librenti MC, et al. Free-insulin profiles after intraperitoneal, intramuscular, and subcutaneous insulin administration. Diabetes Care 1986;9:575-578.
16. The DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986.
17. U.K. Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998;353:837-853.
18. The DCCT/EDIC research group. N Engl J Med 2000;342:381-389.
19. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin dependent diabetes mellitus: A randomized prospective six year study. Diabetes Res Clin Pract 1995;28:103-117.
20. Klein R, Klein BE. Relation of glycemia control to diabetic complications and health outcomes. Diabetes Care 1998;21 (Suppl):C39-43.
21. Shichiri M, Kishikawa H, Ohkubo Y, et al. Long term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000;23:B21-B29.
22. Hirsch IB, Farkas-Hirsch R, Skyler JS. Intensive insulin therapy for treatment of type I diabetes. Diabetes Care 1990;13:1265-1283.
23. Pampanelli S, Fanelli C, Lalli C, et al. Long-term intensive insulin therapy in IDDM. Diabetologia 1996;39:677-686.
24. Heinemann L, Linkeschova R, Rave K, et al. Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care 2000;23:644-649.
25. Trümper BG, Reschke K, Molling J. Circadian variation of insulin requirement in insulin dependent diabetes mellitus the relationship between circadian change in insulin demand and diurnal patterns of growth hormone, cortisol and glucagon during euglycemia. Horm Metab Res 1995;27:141-147.
26. Geffner ME, Frank HJ, Kaplan SA, et al. Early-morning hyperglycemia in diabetic individuals treated with continuous subcutaneous insulin infusion. Diabetes Care 1983;6:135-139.
27. Kerner W, et al. Studies on the pathogenesis of the dawn phenomenon in insulin-dependent diabetic patients. Metabolism 1984; 33:458-464.
28. Campbell PJ, et al. Sequence of events during development of the dawn phenomenon in insulin-dependent diabetes mellitus. Metabolism 1985;34:1100-1104.
29. Van Cauter E, Polonsky KS , Scheen AJ. Roles of Circadian rhythmicity and sleep in human glucose regulation. Endocr Rev 1997;18:716-738.
30. ADA Position Statement. Pancreas transplantation for patients with Type 1 diabetes. Diabetes Care 2003;26:S120.
31. Jaremko J, Rorstad O. Advances toward the implantable artificial pancreas for treatment of diabetes. Diabetes Care 1998;21;444-450.
32. Garg SK, Walker AJ, Hoff HK, et al. Glycemic parameters with multiple daily injections using insulin glargine versus insulin pump. Diab Tech and Therapeutics 2004;6:9-15.
33. Tsui E, Barnie A, Ross S, et al. Intensive insulin glycemic parameters with multiple daily injections using insulin glargine versus insulin pump therapy with insulin lispro: A randomized trial of continuous subcutaneous insulin infusion versus multiple daily insulin injection. Diabetes Care 2001;24:1722-1727.
34. Raskin P, Bode B, Marks J, et al. Continuous subcutaneous insulin infusion and multiple daily injection therapy are equally effective in Type 2 diabetes. Diabetes Care 2005;26: 2598-2603.
35. Pramming S, Thorsteinsson B, Bendtson I, et al. Nocturnal hypoglycaemia in patients receiving conventional treatment with insulin. Br Med J (Clin Res Ed). 1985;291:376-379.
36. Francis AJ, Home PD, Hanning I, et al. Intermediate acting insulin given at bedtime: Effect on blood glucose concentrations before and after breakfast. Br Med J (Clin Res Ed) 1983;286:1173-1176.
37. Ratner R, Hirsch I, Neifing J, et al. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes: U.S. Study Group of Insulin Glargine in Type 1 Diabetes. Diabetes Care 2000;23:639-643.
38. Rossetti P, Pampanelli S, Fanelli C, et al. Intensive replacement of basal insulin in patients with Type 1 diabetes given rapid-acting insulin analog at mealtime: A 3-month comparison between administration of NPH insulin four times daily and glargine insulin at dinner or bedtime. Diabetes Care 2003;26:1490-1496.
39. Hamann A, Matthaei S, Rosak C, et al. A randomized clinical trial comparing breakfast, dinner, or bedtime administration of insulin glargine in patients with type 1 diabetes. Diabetes Care 2003;26:1738-1744.
40. Leese G, Wang J, Broomhall J, et al. Frequency of severe hypoglycemia requiring emergency treatment in Type 1 and Type 2 diabetes: A population-based study of health service resource use. Diabetes Care 2003;26:1176-1180.
41. Kaplan W, Rodriguez L, Smith O, et al. Effects of mixing glargine and short-acting insulin analogs on glucose control diabetes care 2004;27:2739-2740.
42. Abraira C, Colwell JA, Nuttall FQ, et al. Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM): Results of the feasibility trial. Diabetes Care 1995;18:1113-1123.
43. Segel SA, Paramore DS, Cryer PE. Hypoglycemia-associated autonomic failure in advanced Type 2 diabetes. Diabetes 2002;51:724-733.
44. Pyorala K, Laasko M, Uusitupa M. Diabetes and arteriosclerosis: an epidemiologic view. Diabetes Metab Rev 1987;3:463-524.
45. Fontbonne AM, Eschwege EM. Insulin and cardiovascular disease. Paris prospective study. Diabetes Care 1991;14:461-469.
46. Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Eng J Med 1996;334:952-957.
47. Malmberg K, Ryden L, Efendic S, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): Effects on mortality at 1 year. J Am Coll Cardiol 1995;26:57-65.
48. Malmberg K, for the DIGAMI Study Group. Prospective randomized study of intensive insulin treatment on long-term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ 1997;314:1512-1515.
49. Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: Glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004;141:421-431.
50. Khaw K, Wareham N, Bingham S, et al. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: The European prospective investigation into cancer in Norfolk. Ann Intern Med 2004;141:413-420.
51. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;19:1359-1367.
52. Black CT, Hennessey PJ, Andrassy RJ. Short-term hyperglycemia depresses immunity through nonenzymatic glycosylation of circulating immunoglobulin. J Trauma 1990;30:830-832.
53. Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: Role of oxidative stress. Circulation 2002;106:2067-2072.
54. Calles-Escandon J, Cipolla M. Diabetes and endothelial dysfunction: A clinical perspective. Endocr Rev 2001;22:36-52.
55. Pugh JA, Wagner ML, Sawyer J, et al. Is combination sulfonylurea and insulin therapy useful in NIDDM patients? A meta-analysis. Diabetes Care 1992;15:953-959.
56. Riddle MC, Hart JS, Bouma DJ, et al. Efficacy of bedtime NPH insulin with daytime sulfonylurea for subpopulation of type II diabetic subjects. Diabetes Care 1989;12:623-629.
57. Rosenstock J, Schwartz SL, Clark CM Jr, et al. Basal insulin therapy in type 2 diabetes. Diabetes Care 2001;24:631-636.
58. Johnson JL, Wolf SL, Kabadi UM. Efficacy of insulin and sulfonylurea combination therapy in type II diabetes. A meta-analysis of the randomized placebo-controlled trials. Arch Intern Med 1996;156:259-264.
59. Wright A, Burden F, Paisey R, et al. Sulfonylurea inadequacy: Efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care 2002;25:330-336.
60. Kabadi MU, Kabadi U. Effects of Glimepride on insulin secretion and sensitivity in patients with recently diagnosed Type 2 diabetes mellitus. Clin Therapeutics 2004;26:63-69.
61. Riddle MC. Timely addition of insulin to oral therapy for type 2 diabetes. Diabetes Care 2002;25;395-396.
62. Riddle MC, Schneider J. Beginning insulin treatment of obese patients with evening 70/30 insulin plus glimepiride versus insulin alone. Diabetes Care 1998;21:1052-1057.
63. Raskin P, Rendell M, Riddle MC, et al. A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated Type 2 diabetes. Diabetes Care 2001;24:1226-1232.
64. Wulffelé M, Kooy A, Lehert P, et al. Combination of insulin and metformin in the treatment of Type 2 diabetes. Diabetes Care 2002;25:2133-2140.
65. Yki-Järvinen H. Combination therapies with insulin in Type 2 diabetes. Diabetes Care 2001;24:758-767.
66. Kabadi UM, Kabadi MU. Daily insulin dose in combination with metformin and/or glimepride in Type 2 diabetes mellitus. Diabetes 2002;51:A102.
67. Lindstrom T, Nystrom FH, Olsson AG, et al. The lipoprotein profile differs during insulin treatment alone and combination therapy with insulin and sulfonylureas in patients with Type 2 diabetes mellitus. Diabetic Med 1999;16:820.
68. Costa B, et al. Medication consumption in diabetes mellitus. Economics and effectiveness of insulin and sulfonylurea combination therapy compared with conventional two-daily doses. Med Clin (Barc) 1998;111:568.
69. Riddle MC, Rosenstock J, Gerich J. The Treat-to-Target Trial: Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26:3080-3086.
70. Yki-Jarvinen H, Dressler A, Ziemen M. Less nocturnal hypoglycaemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 study group. Diabetes Care 2000;8:1130-1136.
71. American Diabetes Association Position statement. Gestational diabetes mellitus. Diabetes Care 2001;24 Suppl1:S77.
72. Devlin J, Hothersall L, Wilkis JL. Use of insulin glargine during pregnancy in a Type 1 diabetic woman. Diabetes Care 2002;25:1095-1096.
73. Rayburn W, Piehl E, Lewis E, et al. Changes in insulin therapy during pregnancy. Am J Perinatol 1985:271-275.
74. Weiss PA, Hofmann H. Intensified conventional insulin therapy for the pregnant diabetic patient. Obstet Gynecol 1984;64:629-637.
75. Jovanovic L, Knopp R, Brown Z, et. Declining insulin requirement in the late first trimester of diabetic pregnancy. Diabetes Care 2001;2:1130-1136.
76. Benjamin E. Case study: Glycemic control in the elderly: Risks and benefits. Clin Diabetes 2002;20:118-121.
77. Jacober SJ, Sowers JR. An update on perioperative management of diabetes. Arch Intern Med 1999;159:2405-2411.
78. Pezzarossa A, Taddei F, Cimicchi MC, et al. Perioperative management of diabetic subjects. Subcutaneous versus intravenous insulin administration during glucose-potassium infusion. Diabetes Care 1988;11:52-58.
79. Fisher JN, Shahshahani MN, Kitabchi AE. Diabetic ketoacidosis: Low-dose insulin therapy by various routes. N Engl J Med 1977;297:238-241.
80. Clinical Guidelines, ADA 2004. Diabetes Care 27:S15-S35.
81. Diabetes Prevention Trial-Type 1 Diabetes Study Group: Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002;346: 1685-1691.
82. Kabadi U, et al. Weight gain, improvements in metabolic profiles and immunogenicity with insulin or sulfonylurea administration in AIDS. Clin Drug Invest 2004;24:287-294.
83. Fritsche A, Schweitzer MA, Haring HU; 4001 Study Group. Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial. Ann Intern Med 2003;138: 952-959.
84. Korytkowski M, Thomas A, Reid L, et al. Glimepiride improves both first and second phases of insulin secretion in Type 2 diabetes. Diabetes Care 2002; 25:1607-1611.
85. Raskin P, et al. Initiating insulin in Type 2 diabetes. Diabetes Care 2005;28:260-265.
86. Malone JK, et al. Combined therapy with insulin lispro mix 75/25 plus metformin: A 16-week randomized, open-label crossover study in patients with Type 2 diabetes beginning insulin therapy. Clin Therapeutics 2004;26:2034-2044.
87. Janka H, et al. Starting insulin for Type 2 diabetes with insulin Glargine added to oral agents vs twice daily pre-mixed insulin alone. Diabetes Care 2005;28:252-259.