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Abstract

Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type- 1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes.

Figure 1 Schematic representation of human proinsulin. C-peptide, a 31 amino acid (aa) residue peptide, is depicted between A (21 aa) and B (30 aa) chains. In healthy individuals, both insulin and C-peptide are secreted in equimolar amounts from pancreatic β cells. In patients with diabetes, pancreatic β cells are destroyed by auto-immunity resulting in deficiency of both insulin and C-peptide. Although diabetic patients may routinely receive insulin injections to compensate the insulin deficit, no replacement for C-Peptide is currently administered to diabetic patients. Prohormone Convertase (PC 1/3 and PC 2) cleavage sites necessary for the removal of C-peptide from insulin are also shown.

Figure 2 Molecular mechanism of glucose induced insulin secretion. When glucose enters into pancreatic β cells through Glucose Transporter-2 (GLUT-2), it gets phosphorylated to glucose 6-phosphate by GlucoKinase (GK). Phosphorylated glucose enters into glycolytic pathway and electrons are transported through the Electron Transport Chain in mitochondria yielding ATP. Increased ATP/ADP ratio and closure of ATP sensitive K channels (K Ch) lead to membrane depolarization. Change in membrane potential (depicted as a skull) opens up voltage gated Ca2+ channels (Ca Ch) causing influx of Ca2+ into pancreatic β cells. Increased cytosolic Ca2+ concentration facilitates the fusion of insulin-containing secretory vesicles with plasma membrane releasing insulin. Nu, nucleus; Mt, mitochondria; ER, endoplasmic reticulum.

Figure 3 Molecular structure of fast and long acting insulin analogs. P(B28) and K(B29) residues at the COO− terminus of B chain are reversed in Insulin Lispro. Insulin Aspart has D residue in place of P at B28. K(B29) residue is changed to E, and N(B3) is substituted with K in Insulin Glulisin. Glargine has an addition of two dibasic aa (RR) at the COO− end of B chain (B31 and B32) in addition to a substitution of N to G at position A21. B29K residue is attached to a fatty acid (myristic acid) in Insulin Detemir, which lacks T(B30) (LysB29 (N-tetradecanoyl)des(B30)). In Insulin Degludec, however, T(B30) is deleted and K(B29) has been coupled to a fatty acid (hexadecanedionic acid) via E (Glu) bridge.

In conclusion, there is no question that insulin and insulin analogs are more efficacious in reducing HbA1c levels (and managing T1DM and T2DM) compared with oral antidiabetics. Because of the limited efficacy of noninsulin diabetic medications, insulin analogs are expected to facilitate the transition between oral agents and insulin therapy more successfully compared with human insulins. Despite the improvements in efficacy, safety, mechanisms of delivery and even patient flexibility and convenience, some clinical challenges still exist. In terms of total direct healthcare costs, insulin analogs and older insulin treatments are equally expensive, as the treatment with insulin analogs is associated with increase in quality of life and life expectancy. In addition, reduced risk of hypoglycemia, greater convenience and, in some instances, less weight gain are among the many benefits offered by insulin analogs compared with human insulins. Accordingly, fast-acting insulin analogs can mirror endogenous insulin action profile more closely exhibiting better postprandial glucose management properties than regular human insulin. Moreover, long-acting insulin analogs possess relatively flat time-action profiles lasting up to 24 h. This mode of action mimics endogenous basal insulin profile better than NPH insulin causing less nocturnal (bedtime) hypoglycemia. Expectedly, if/when insulin degludec is approved by the US FDA, it may soon overtake the long-acting basal insulin market currently dominated by insulin glargine (Lantus), since it confers a more flexible dosing schedule and reduced risk of hypoglycemia. Ultimately, more scientific data on the clinical efficacy of insulin degludec including cardiovascular outcome and the safety profile is needed to determine its potential impact in diabetes treatment.