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A Insulin Therapy for Type 2 Diabetes: Rescue, Augmentation, and Replacement of Beta-Cell FunctionA  This is a corrected version of the article that appeared in print. Twenty-seven percent of persons with type 2 diabetes use insulin therapy, but less than one half achieve the recommended A1C level of 7 percent or less.1 These statistics suggest that suboptimal insulin therapy is too common. NICE has developed a comprehensive care pathway for managing hyperglycaemia using up-to-date guidelines and updated recommendations on blood glucose lowering therapy, including conventional oral therapy, newer agents and insulins1.
The guidelines recommend that all appropriate components of medical care, including pharmacological interventions, lifestyle measures, self-monitoring, and education should be aggressively implemented at the time of diagnosis to achieve and maintain glucose control targets5. View the current treatment and management strategies for diabetes type 2 with special attention paid to the treatment of patients with impaired renal function.
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AbstractType 2 diabetes mellitus is on the rise, yet glycemic control continues to elude patients—and their physicians. The inability to achieve glycemic control in the majority of these patients, when combined with the disorder's increasing prevalence, has implications for increasing morbidity and mortality among patients with diabetes.2,10 Clearly, diabetes care must be optimized to improve patient outcomes.
Since its discovery in the 1920s, insulin has been a cornerstone of diabetes care.11 However, for insulin therapy to be effective in treating patients with type 2 diabetes, physicians need to convey to patients, especially those in whom diabetes has been recently diagnosed and those who are not achieving glycemic control with oral drug therapy, that insulin therapy is effective and well-tolerated. The unwillingness of physicians and their patients to initiate insulin therapy according to conventional recommendations has been referred to as “psychological insulin resistance.”14 Such reluctance may prolong the time that glycemia is not optimally controlled, therefore increasing the risk of neuropathic, microvascular, and macrovascular complications. Because perceived notions regarding insulin therapy can have detrimental effects, physicians' attitudes, beliefs, and practices regarding intensive glycemic control are essential to successful clinical outcomes.
To achieve glycemic control, the AACE and the ACE2 recommend the early use of insulin in the form of basal insulin (with or without oral antidiabetic agents) or basal bolus insulin therapy (premixed insulin preparations are recommended for those who require additional insulin during meals). The third approach to overcoming patient concerns about frequent injections is to use insulin pen devices instead of conventional vial-and-syringe delivery.
Indications for exogenous insulin therapy in patients with this condition include acute illness or surgery, pregnancy, glucose toxicity, contraindications to or failure to achieve goals with oral antidiabetic medications, and a need for flexible therapy. Absolute and increasing blood glucose levels stimulate insulin release.2 The postprandial glucose influx can be 20 to 30 times higher than hepatic production between meals. Although no insulin has a category A pregnancy classification, regular and NPH insulin have been used extensively in pregnant women.
The insulin regimen should be tailored to the patient’s degree of hyperglycemia, the risks associated with hypoglycemia, comorbid conditions, the ability to adhere to a routine and understand and master the information and skills, and the cost. They later simplified the algorithm to a two-tier, three-step approach based on well-validated core therapies supported by less-well validated therapies. Spellman, PhD, DO, Divisions of Internal Medicine and Endocrinology, University of North Texas Health Science Center at Fort Worth, 855 Montgomery St, Fort Worth, TX 76107-2699. During the past decade, the use of insulin monotherapy has decreased while the use of oral antidiabetic agents (either alone or in combination with insulin injections) has increased.


Changes in treatment therapies for adults with type 2 diabetes mellitus based on National Health and Nutrition Examination Survey (NHANES) results.8,9 (Copyright 2004 American Diabetes Association from Diabetes Care, Vol.
Physicians should discuss insulin therapy as an effective treatment option with their patients. The AACE and ACE guidelines2 recognize the effectiveness of insulin therapy, the decreased risk of hypoglycemia, and the simplified therapy with minimal daily injections associated with insulin analogs. For example, in patients with impaired glucose tolerance or insulin resistance, recent studies18,19 have demonstrated that thiazolidinediones can substantially delay or prevent the progression of type 2 diabetes mellitus. The key consideration is to balance the individual's need for glycemic control with his or her tolerance for performing self-injection. Insulin pens make self-injection simpler and more convenient and provide increased dosing accuracy.
Phase 1 insulin release, lasting 10 minutes, suppresses hepatic glucose production and facilitates phase 2 release, which lasts two hours and covers mealtime carbohydrates.
The most common indication for insulin therapy is failure to achieve glycemic control with diet, exercise, and oral medications.
The continued prevalence of the disorder, changes in prescribing patterns, and recent data indicating that only one third of patients with type 2 diabetes mellitus achieve glycemic control underscore the need for physicians to reevaluate the clinical management of this now common disorder. For some patients, starting an insulin regimen with a single daily injection may be the best approach. Clinical trials have shown that patients over-whelmingly prefer these devices compared with conventional insulin delivery23,24 and that this alternative delivery method may lead to improved adherence with daily insulin therapy and improved glycemic control. Between meals, a low continuous insulin level, called basal insulin, serves ongoing metabolic needs.The normal beta cell responds in a linear fashion to blood glucose levels.
Although three oral agents can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and expense.
Insulin analogs provide flexibility in the delivery of insulin therapy for this population.
Also, the use of basal insulin either alone or in combination with an oral antidiabetic agent such as metformin provides considerable flexibility. The slope of this response is steeper after fasting and flattened following prolonged exposure to high glucose levels. However, in the Steno-2 study,14 a combination of glycemic, lipid, and blood pressure control reduced mortality by 50 percent compared with usual therapy.
Although potential barriers and complications to initiation exist, patients should understand that achieving and maintaining glycemic control reduces the risk of long-term complications as a result of type 2 diabetes mellitus. This loss of responsiveness to glucose levels, which may be reversible in the earlier stages, also is called beta-cell exhaustion or glucose toxicity.3In type 2 diabetes, phase 1 release is absent, and phase 2 release is delayed and inadequate. In the UKPDS,13 patients taking insulin gained 4 kg (8 lb, 13 oz) more than those treated with diet therapy over 10 years.


Physicians are encouraged to actively identify and address patient concerns about this treatment modality.
The sharp spike of mealtime insulin release occurring in normal persons (white background in Figure 1) is delayed, prolonged, and insufficient in amount in patients with type 2 diabetes. Patients who have irregular hours and meals may find that insulin glargine and rapid-acting analogues provide more flexibility, while those with a set routine can do well with the traditional insulins.Schedule patients for follow-up within one week to adjust insulin doses and provide more education.
Maintain contact with the patient through office visits, telephone calls, fax, or secure e-mail every three to seven days until blood sugar level is at the goal.Always ask for the self-monitoring blood glucose log. The United Kingdom Prospective Diabetes Study (UKPDS)5 demonstrated that this function continues to deteriorate over time despite treatment with diet, exercise, metformin (Glucophage), sulfonylureas, or insulin. About 50 to 60 percent of the total daily insulin requirement should be a basal type, and 40 to 50 percent should be a bolus type. The mealtime dose is the sum of the corrective dose plus the anticipated requirements for the meal and exercise. A more accurate estimate is provided by levels of C-peptide, a byproduct of insulin production with a half-life of 30 minutes. Adjustments should be made systematically, starting with the fasting, then the preprandial and, finally, the postprandial glucose levels.
Basal therapy with glargine insulin provides similar to lower A1C levels with less hypoglycemia than NPH insulin.
Insulin aspart and insulin lispro provide similar A1C levels and quality of life, but lower postprandial glucose levels than regular insulin.
First, their absorption profiles are erratic, creating day-to-day fluctuations in glycemic control.9 Second, their delayed onset of action and peak activity requires coordination of injection and meals. Regular insulin must be injected 30 to 60 minutes before the meal to match postprandial glucose influx.
NPH may cause hypoglycemia during its peak at four to 10 hours after injection unless the patient remembers to eat. Augmentation also can be provided at mealtime using regular insulin (Figure 5), aspart, or lispro27,28 adjusted to maintain two-hour postprandial glucose levels of 180 mg per dL (10 mmol per L) or less.
The most convenient basal-bolus regimen uses split-mixed injection of NPH and regular insulin before breakfast and dinner but requires rigid adherence to a set meal size and time. The morning NPH may not provide adequate coverage for lunch, and the evening NPH may cause nocturnal hypoglycemia.
Regimens include NPH and regular insulin, NPH with aspart or lispro, or glargine and aspart or lispro (Figure 7) .



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