Diabetes mellitus is a disease characterized by metabolic dysregulation, in particular by abnormal glucose metabolism, accompanied by characteristic long-term complications. Specific complications of diabetes include retinopathy, nephropathy, and neuropathy. Patients with all forms of diabetes of sufficient duration, including type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), are vulnerable to these complications, which cause severe morbidity. These are microvascular complications. High plasma glucose levels are the cause of the microvascular complications of diabetes. Say no to plagiarism. Get a tailor-made essay on "Why Violent Video Games Shouldn't Be Banned"? Get an original essay To achieve glycemic goals in patients with type 2 diabetes, multiple pharmacological agents, including sulfonylureas, meglitinides, metformin, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase IV (DPP-4) inhibitors are available ), the glucagon-like peptide 1 (GLP-1) receptor agonist, and insulin. These agents can be used individually or in combination to achieve desired glycemic control. Unlike patients with type 1 diabetes who do not have significant insulin secretion and therefore require insulin therapy from the onset of the disease, in patients with type 2 diabetes insulin resistance with hyperinsulinemia is an important feature in the first stages of the disease. People with type 2 diabetes mellitus therefore benefit from measures to improve insulin sensitivity such as dietary calorie restriction, exercise and weight control in the early stages of the disease in combination with oral agents such as insulin sensitizers and insulin secretagogues to reach your glycemic target. With the progression of type 2 diabetes there is eventually a progressive loss of pancreatic beta cell function and a reduction in endogenous insulin secretion. At this stage, most patients will require exogenous insulin therapy to achieve optimal glucose control. Important clinical studies have been able to establish the fact that optimal glycemic control can prevent/delay the progression of complications in people with diabetes mellitus1. The findings of these studies strategically position insulin as a very important agent for reducing microvascular complications1,2. Data from the United Kingdom Prospective Diabetes Study (UKPDS) suggest that early treatment with insulin reduces macrovascular risk in type 23 diabetes mellitus. These studies aim to achieve glycemic control below which no complications would occur. However, better glycemic control was associated with a reduction in the risk of complications across the entire glycemic range (“the lower the better”) in the UKPDS4. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, a higher mortality was recorded in the intensive blood glucose treatment arm with target HbA1C <6.0% compared to the standard therapy group with target HbA1C between 7.0 and 7.9% 5. In the intensive arm, more episodes of hypoglycemia were recorded, hence the increase in mortality recorded5. No additional benefit was recorded by lowering HbA1C <6.5% in the KUMAMOTO 2 study. Choosing among the wide variety of hypoglycemic interventions currently available could represent a challenge for the healthcare professional and patients in terms of efficacy, tolerability and cost of various treatments for diabetes. However, this should not be true since the reduction in risk of long-term complications was related to the levels ofglycemic control achieved, rather than a specific hypoglycemic agent 1. In the Steno-2 study, very few patients achieved target HbA1C values ​​of 6.5% compared to the large number of patients who achieved intensive blood pressure and lipid targets serum 6. The challenges of initiating and intensifying insulin therapy are quite enormous and could be daunting for healthcare providers. This review contains an overview of currently available insulin preparations and a description of the merits and demerits of the various regimens commonly used for the initiation and intensification of insulin therapy in patients with type 2 diabetes. Our goal is to assist clinicians in designing of individualized management plans for insulin therapy in patients with type 2 diabetes. The rationale of insulin therapy in type 2 diabetes Three main pathophysiological abnormalities contribute to hyperglycemia in type 2 diabetes: excessive hepatic glucose production, impaired pancreatic secretion of insulin and peripheral resistance to insulin action occurring primarily in the liver and muscle tissue1. Of these, peripheral resistance to insulin action and impaired pancreatic beta cell secretion are early and primary abnormalities, while increased hepatic glucose production is a late and secondary manifestation. Early in the disease, patients with type 2 diabetes compensate for increased insulin resistance at the tissue level by increasing insulin secretion from pancreatic beta cells. When this compensation is no longer adequate to overcome insulin resistance, blood glucose levels begin to rise. Over the course of the disease, however, insulin levels slowly begin to decline, and ultimately, most patients with type 2 diabetes mellitus are unable to achieve optimal glycemic control with oral agents1. At this stage the introduction of insulin is inevitable. Human insulin and its analogues Insulin therapy with conventional prandial and basal preparations presents numerous drawbacks. First, the absorption of regular human insulin from the subcutaneous tissue is slow, and the metabolic action takes effect only 30-60 minutes after injection and peaks after 2-3 hours. Consequently, treatment with regular insulin is associated with postprandial hyperglycemia and an increased risk of late postprandial hypoglycemia. Second, conventional NPH basal insulin has a distinct peak hypoglycemic effect, has a duration of action significantly less than 24 hours, and is absorbed from the subcutaneous tissue at variable rates. These pharmacodynamic limitations predispose users to elevated pre-breakfast glucose levels and nocturnal hypoglycemia 7,8. To overcome these difficulties, insulin analogues with an amino acid sequence modified from the human insulin molecule have been developed. The three fast-acting analogues (aside, glulisine, lispro) are absorbed more rapidly than regular insulin due to reduced self-association. Their onset of action occurs within 15 minutes of subcutaneous injection and they have a faster and greater peak of action. Long-acting insulin analogues (detemir and glargine) have a limited peak effect and a longer average duration of action than NPH insulin (with glargine having a slightly longer action than detemir)9- 11. The pathophysiological process in type 2 diabetes mellitus leaves the patient with residual insulin production on the background of insulin resistance. Interestingly, long-acting insulin analogs have pharmacokinetics that closely mimic secretionphysiological nature of insulin in the body. When to start insulin therapy? This question will arise at some point in the management of patients with type 2 diabetes mellitus, a progressive and chronic disease. The answer is not simple. It leaves room for controversy. Oral medications are traditionally introduced gradually, reserving insulin as the final step in the management of type 2 diabetes mellitus. It may take up to 10-15 years after diagnosis before insulin is finally introduced. Fears of painful injections, weight gain, and hypoglycemia hinder early initiation of insulin therapy by both physicians and patients13,14. Negative beliefs about insulin treatment and other socio-cultural factors also influence patients' willingness to accept insulin14, 15. This predisposes the patient to long-term complications due to exposure to many years of uncontrolled hyperglycemia16. This, therefore, requires a proactive approach to treatment failure. Lowering blood sugar improves insulin resistance and insulin secretion17. Early initiation of insulin therapy in a patient newly diagnosed with type 2 diabetes mellitus restores and maintains β17 cell function. We advocate that insulin should be initiated when the stepwise approach has failed to achieve the goal of HbA1C <7%18. This initiation should be rapid when HbA1C <7% is not achieved after 2-3 months of dual oral therapy at the maximum dose. For patients who are intolerant to one or more oral hypoglycemic agents and who do not achieve glycemic control with oral monotherapy, as well as those with a personal preference, early initiation of insulin therapy is indicated. Interestingly, the rapid addition of insulin therapy is supported by numerous studies showing improved treatment satisfaction and quality of life for type 2 diabetic patients initiated on insulin19,20. How to start insulin therapy? Good glycemic control was achieved in the majority of patients with type 2 diabetes mellitus in treat-to-target clinical trials when basal insulin was added to their oral antidiabetic agents21-23. However, it should be noted that the benefit of long-acting insulin analogues lies in the reduction of nocturnal hypoglycemia24. According to the ADA/EASD algorithm for the management of type 2 diabetes, insulin could be initiated with NPH insulin once daily or with a long-acting insulin analog18. A meta-analysis including six randomized comparisons between NPH and glargine found that event rates for self-monitoring blood glucose (SMBG) confirmed symptomatic hypoglycemia <65 mg/dl of only 138 and 91 events per 100 patients- year for these insulins, respectively, in insulin-naïve type 2 diabetic patients who achieved an A1C of 7.0%25. NPH, insulin glargine, and determina have been used as basal insulin to achieve glycemic control in patients with type 2 diabetes. While this may be desirable, clinicians should not ignore the cost implications of new insulins for the patient. In Africa (and Nigeria), the cost of insulin has been a barrier to the acceptance of insulin therapy, apart from socio-cultural issues15. NPH is cost-effective and insulin therapy in type 2 diabetes can be initiated with NPH. The other issue to consider is the frequency of basal insulin dosing. In a treat-to-target study with twice-daily administration of detemir, an A1C endpoint of 6.8% was achieved.22 In other studies, a second daily injection of detemir was required in34-55% of study subjects due to dinner -hyperglycemia or nocturnal hypoglycemia. 23,26 In the only reported study evaluating the efficacy of once-daily insulin detemir, A1C remained above the currently recommended glycemic goal with an endpoint level of 7.4%, both for 'insulin NPH than for detemir, 27 compared to an A1C at the end of the study. <7.0% with glargine and NPH once daily in the original Treat-to-Target study.21 In the ACCORD study,5 the finding of increased mortality in the intensive glucose-lowering therapy group will likely dissuade some providers from promptly lowering the glucose. The ACCORD study included only patients at high risk of cardiovascular disease, in whom low A1C levels were achieved using up to four or five different classes of hypoglycemic drugs. In contrast, in less selected patients treated with stable doses of one or two oral agents, simple titration algorithms targeting fasting blood glucose = 100 mg/dl (= 5.6 mmol/l) can safely achieve an A1C of 7. 0%. 21 A patient-driven algorithm, with patients increasing their insulin dose by 2 to 3 units every 3 days, as long as fasting blood glucose remains above target, is a practical approach that has been shown to be equally or more effective than doctor-guided titration. 28,29 In the timing of once-daily basal insulin regimens, evening NPH administration appears to be superior to morning injection7,19. There are conflicting results in studies examining the injection time of long-acting insulin analogs. When morning and evening injections of insulin glargine were compared in one study, a greater reduction in HbA1c and nocturnal hypoglycemia was observed when insulin glargine was administered in the morning30, whereas in another larger study of identical design no significant difference in timing was found31. Morning administration of insulin detemir was associated with lower daytime glucose levels and a trend towards a reduced risk of nocturnal hypoglycaemia compared to evening injection27. What do all this mean? We can safely conclude from these discrepant data that when nocturnal hypoglycemia limits evening detemir or glargine dose titration, morning dosing may be attempted. There are other options for starting insulin therapy. The Treatment to Target study in type 2 (4-T) diabetes compared various options for initiating insulin treatment. Basal insulin introduced at bedtime has been compared with biphasic insulin twice daily or with prandial insulin before meals26. Regimens using biphasic or prandial insulin have been found to reduce HbA1c to a greater extent than baseline, but are associated with greater risks of hypoglycemia and greater weight gain26. The reduction in HbA1c with biphasic insulin is equivalent to mealtime insulin. However, there is greater weight gain and greater hypoglycaemia compared to basal insulin, but less for both than prandial insulin26. Initiating prandial insulin therapy is not the first-line approach when initiating insulin therapy in type 2 diabetes mellitus. This was given credence in the study comparing once-daily insulin glargine with insulin lispro three times daily in insulin-naïve patients32. Therefore, adding insulin once basal will reduce the frequency of injections and promote patient acceptability of initiating insulin therapy. Combining basal insulin with oral agents has been shown..