13.Bluetree.cdr Type 2 diabetes mellitus (T2DM) is characterized by relative insulin deciency, decreased peripheral and hepatic 1sensitivity to insulin and raised plasma glucose levels . T2DM treatment begins with lifestyle interventions, before progressing to pharmacological interventions with advancing disease. Despite the introduction of numerous anti- hyperglycemic medications, many patients with T2DM require insulin, and basal insulin continues to be frequently used either as rst-line insulin treatment or as part of multiple daily 2injection regimens . Oral hypoglycemic agents are effective agents for diabetes management, although secondary drug failure rates of 5-10% are bothersome. The disappointing results with monotherapy especially the worsening metabolic control is often seen within ve years after the initiation of an oral hypoglycemic agent, with more than 50% patients requiring shifting to the insulin-based regimen to achieve 3optimal glycaemic control . Basal insulin therapy is recommended if lifestyle modications and oral antidiabetic agents fail to maintain HbA1c levels <7.5% and has been 4shown to improve glycemic control . This highlights the fact that adequate basal insulin levels are an essential component of diabetes management. The ideal basal insulin should provide a sustained level of insulin, mimicking physiological basal insulin secretion, reproduce physiological basal insulin secretion, thereby restoring glycemic control, without 1hypoglycemia . Such therapy should have relatively at/constant insulin concentration prole over time, no pronounced peak, duration of action of at least 24 h, low within-patient variability in fasting plasma glucose (FPG), a favorable safety prole, including low risk of hypoglycemia 2and weight gain, and be easy to administer and titrate . However, traditional insulin does not fully accomplish this goal. This stimulated the search for insulins with a more prolonged duration of action that could better replicate the 5physiological basal insulin secretory response . This eventually led to the development of basal insulin-like, Neutral (porcine) protamine Hagedorn (NPH) insulin, Lente insulin, insulin detemir, etc. Still, all these variants are also not able to achieve the desired therapeutic insulin levels. For instance, NPH insulin, intermediate-acting insulin, has a duration of action that is considerably less than 24 h and an activity prole that peaks 3–5 h after administration. NPH insulin administered at bedtime results in high insulin levels when insulin requirements are low. This activity prole is not 1ideal as it increases the risk of nocturnal hypoglycaemia . A greater understanding of the protein structure of insulin and the roles of key amino acids has opened up new avenues for the rational design of insulin analogs with more predictable absorption and time–action characteristics. Insulin glargine (IGlar) was the rst long-acting basal analog to be introduced into clinical practice in 2000 and was a breakthrough in the eld of insulin therapy. It continues to be a gold standard of basal insulin treatment and a benchmark for new injectable antihyperglycemic treatments, including newer basal insulin 2analogs . IGlar is a biosynthetic, long-acting, clear human insulin analogue with an acidic pH. Upon subcutaneous injection, IGlar is neutralized and forms microprecipitates that 6release insulin in a constant prole over 24 h . STRUCTURE OF IGLAR IGlar differs from human insulin by the replacement of A21 asparagine with glycine and the addition of two arginine residues at B31 and B32 (GlyA21, ArgB31, and ArgB32). These mutations endow glargine with an isoelectric point of 6.4–6.8, implying that it is easily soluble at acid pH and less soluble at neutral pH. As a result, upon subcutaneous injection, IGlar forms an amorphous precipitate in the subcutaneous tissue, which slowly dissociates, providing a sustained release of 5insulin into the circulation . Once injected, IGlar gets immediately metabolized into two main active metabolites M1 (GlyA21) and M2 (GlyA21, des- ThrB30). The M1 metabolite accounts for approximately 90% of the daily plasma insulin available. This protracted release of glargine from the subcutaneous depot translates into longer bioactivity than either human NPH or human ultra Lente insulin. Thus, IGlar can be administered once daily, unlike the earlier 'intermediate'/'long-acting' insulin 5preparations . IGlar once daily has been shown to achieve superior glycemic control with equivalent or lower rates of hypoglycemia compared with NPH insulin in patients with 4T2DM . CLINICAL EFFICACY OF IGLAR Usage of NPH insulin is most often limited due to the high risk of nocturnal hypoglycemia when taken at bedtime, as its peak of the action occurs 4–6 h post-injection. In contrast, the smoother activity of the long-acting insulin analog, IGlar, allows more exibility in dosing, and its administration is less strictly bound to the time of injection. This is especially important for certain patient populations where hypoglycemia 5poses a greater risk, such as the elderly . Hence, IGlar is approved for administration at any time of day, provided it is 7at the same time each day . To conrm the non-occurrence of hypoglycemia post-IGlar administration, Porcellati et al., 7carried out a study in T2DM insulin-treated patients . The study was carried out in 10 T2DM insulin-treated persons were studied during 24-h euglycemic glucose clamp, after glargine injection (0.4 units/kg s.c.), either in the evening (2200 h) or the INSULIN GLARGINE IN TYPE 2 DIABETES Original Research Paper Dr. Sanjay Mahajan 150 Duplex Apartments B-5 Vasundhara Enclave Delhi-110096 Medicine KEYWORDS : VOLUME-9, ISSUE-3, MARCH-2020 • PRINT ISSN No. 2277 - 8160 • DOI : 10.36106/gjra Dr. Shweta Bhanot Pandit* Pandit Medical Near Mini Stadium Padmnabhpur Durg ( Cg ), 491001 *Corresponding Author Dr Jitendra B Patel Pruthvi Med. Nursing Home & Heart Centre, S. P. Colony, Naranpura, Ahmedabad Dr. Sunil Shirsikar Dwara Hospital, 101, Rajanvan Society Near Centreal Bank, N-9 Hudco Aurangabad, 431003 Dr M. G. Binu Gknm, Avinashi Road, Coimbatore-641028 36 X GJRA - GLOBAL JOURNAL FOR RESEARCH ANALYSIS morning (1000 h). It was concluded from the study that, the pharmacodynamics of insulin glargine differs depending on the time of administration. With morning administration insulin activity is greater in the rst 0–12 h, while with evening administration the activity is greater in the 12–24 h period following dosing. However, glargine pharmacokinetics and plasma C-peptide levels were similar, when analyzed by 24-h clock time independent of the time of administration. Thus, insulin sensitivity in T2DM is affected by circadian rhythm 7rather than glargine per se . Diabetic kidney disease is one of the most frequent microvascular complications related to diabetes mellitus and is the leading cause of end-stage renal disease. Kidneys play an important role in the regulation of glucose homeostasis, because they release a signicant amount of glucose in the post-absorptive state, and they are responsible for approximately one-third of insulin degradation. The progressive loss of kidney function, and its consequent reduction in parenchyma and blood ow, has been associated with a lower capacity of renal glucose release, drug metabolism, and excretion and insulin extraction, resulting in prolonged half-life of some oral antihyper gl ycemic agents and insulin, besides an impaired response to hypoglycemia Thus, glycemic control in patients with chronic kidney disease (CKD) is particularly hard to achieve because of a slower insulin degradation by the kidney. It might modify the long-acting insulin analogue pharmacokinetics, 8increasing its time of action and the risk of hypoglycemia . Betonico et al. examined the efcacy and safety prole of long-acting basal analogues in patients with signicant loss of renal function. A comparison of the glycemic response to treatment with IGlar U100 or NPH insulin in patients with type 2 diabetes mellitus (T2DM) and CKD stages 3 and 4 was done in 34 patients. After 24 weeks, mean HbA1c was found to decrease on IGlar U100 treatment (−0.91%; P < 0.001), however, this benet was not observed for NPH (0.23%; P ¼ 0.93). Moreover, the incidence of nocturnal hypoglycemia was found to be 3 times lower with IGlar than with NPH insulin (P ¼ 0.047). Thus indicating the potential of IGlar U100 in patients 8with T2DM and CKD stages 3 and 4 without resulting in signicant hypoglycemia. Traditionally, basal insulin is initiated on the failure of a standard therapeutic oral anti-diabetic regimen and is given as an additional hypoglycemic agent along with oral anti- diabetics. Eliaschewitz et al., compared the efcacy and safety of IGlar and NPH insulin, both in combination with a once-daily xed-dose of glimepiride, in terms of glycemic control and incidence of hypoglycemia in an open-label, 24- 4week randomized trial in ten Latin American countries . It was found that IGlar and NPH insulin achieved similar HbA1c reductions (adjusted mean difference 20.047; 90% CI 20.232, 0.138; per-protocol analysis). However, conrmed nocturnal hypoglycemia was signicantly lower with IGlar vs. NPH insulin (16.9 vs. 30.0%; p