DPP-4 Enhances The Body: A Case Study

Everybody knows that obesity is a big factor in developing type-2 diabetes, and that part of coping with this metabolic disorder is lifestyle change. If blood glucose does not go down, then medicines are introduced. Some type-2 diabetics even have to administer insulin in order to keep their blood glucose levels

Type 2 diabetes is an increasingly common endocrine disorder. Therefore, it is characterized by chronic hyperglycemia and results in multiple tissue compartments that include microvascular and macrovascular implications. This article discusses subcutaneous dulaglutide, leading to its approval for type 2 diabetes. Dulaglutide is a recombinant GLP-1 Fc fusion protein that links human GLP-1 analog peptide and a variant of human lgG4 Fc fragment. Thus, an analog of GLP-1 has developed long lasting effects and has proven to be effective in type 2 diabetes. It offers greater convenience to the patient. It consists of DPP-IV that protects GLP-1 analog which is covalently linked to human heavy chain by a small peptide linker.

Incretin based drugs have proven to be effective glucose-lowering agents (Butler et al, 2013). But there have been concerns with respect to the long-term consequences of using such therapies. The issues raised were regarding their causal relationship with acute pancreatitis (AP). There are clearly conflicting evidence that have been presented in preclinical studies and in epidemiologic studies which suggest an association which may or may not be a causal relationship between these drugs and AP. (Butler et al, 2013)

The clinical study outcome showed that insulin degludec compared similarly with insulin glargine in both type 1 and type 2 diabetic patients on the reductions of both HbA1c and fasting plasma glucose levels. However, when the amount of episodes of hypoglycemia were compared, the patients taking insulin degludec showed an increased reduction of hypoglycemic events, anywhere from 18% to 25% fewer incidences (Stockley, 2014, p. 18). This finding is extremely important and beneficial because the main reason cited for

Lixisenatide, a once daily prandial GLP-1 receptor agonist, has an strong effect on lowering postprandial glucose by reducing glucagon release and delaying gastric emptying. Lixisenatide and insulin glargine have similar features which allows them to be mixed and delivered through

Prevention and slowing the progression of DPN via glucose control has been demonstrated to be effective in patients with type 1 diabetes, but may not be as effective in patients with type 2 diabetes (Callaghan BC 201211). Other studies found no correlation between glycated hemoglobin (HbA1C) with mean of 6.9% and the severity of DPN (Owolabi MO 201212). Diabetic patients are more susceptible to dyslipidemia and metabolic syndrome. Those patients have body mass index (BMI) ≥30Kg/m2, abnormal glucose metabolism with insulin resistance, high low-density-lipoprotein (LDL), total cholesterol (TC), triglycerides (TG), and low high-density lipoprotein (HDL). Those abnormal findings expose patients to atherosclerotic changes and microvascular complications together with hypertension and cardiovascular diseases (Mooradian AD

Type 2 diabetes results from a multitude of defects: impaired insulin secretion, insulin resistance, and defects in GLP-1 secretion and action. Prior to the onset and throughout the course of the disease, beta cell function and pancreatic mass deteriorate; causes may be lipotoxicity, glucose toxicity, increased age, genetics, insulin resistance, and incretin deficiency. Insulin resistance takes place in the liver, adipose, and skeletal tissues (1), ultimately leading to decreased peripheral uptake and hyperglycemia. In the liver, lack of insulin action results in gluconeogenesis and glycogenolysis, further potentiating the hyperglycemia. In fat cells, decreased GLUT4 leads to excessive release of free fatty acids and adipocytokines (2). Because

Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) occupy an increasing place in the armamentarium of drugs used for the management of hyperglycemia. It also offer new opportunities for a personalized medicine in patients with Type 2

Dapaglifozin and canagliflozin are the first PBS-listed agents from a new class of oral antidiabetics agents known as SGLT2 inhibitors. This class represents a novel insulin-independent approach for treatment of type 2 diabetes that relies on the role of the kidneys in glucose homeostasis. SGLT2 is a low-affinity, high-capacity sodium-coupled glucose transporter located on the luminal side of the renal proximal tubule and accounts for most glucose reabsorption in the kidneys (Pajor et. al., 2008).

Semaglutide is a glucagon-like peptide-1 (GLP-1) agonist, which is a new antidiabetic drug that has been studied to show therapeutic benefits in non-insulin dependent diabetics and in patients with preexisted heart disease. Type 2 diabetes often leads to cardiovascular complications especially atherosclerosis which can lead to a myocardial infarction. GLP-1 receptors are widely presented in different tissues including the cardiovascular and pancreatic tissues. GLP-1 agonist performs many functions including stimulating pancreatic beta-cells to release insulin, suppressing glucagon secretion, promoting blood glucose balance, delaying gastric emptying, and decreasing appetite. Excess sugar in the blood can prevent glucose absorption into cells

The DPP 4 inhibitors come in the class of incretin based therapies for type 2 diabetes. The incretin effect is generally blunted in type 2 diabetes patients.16 The two main incretin hormones responsible for blood glucose regulation are GLP-1 (glucagon like peptide-1) and GIP ( glucose dependent insulinotropic peptide). These two hormones are secreted when carbohydrates and fats are consumed and they result in increased glucose dependent insulin secretion or postprandial insulin release and decreased glucagon secretion. Both of these hormones tend to be rapidly metabolized in the circulation by the enzyme DPP 4 (dipeptidyl peptidase). Type 2 diabetes mellitus is characterized by decreased insulin sensitivity and progressive loss of pancreatic beta cell insulin secretion .The DPP 4 inhibitors block the breakdown of naturally occurring GLP 1 by competitively inhibiting the binding of GLP 1 to DPP .The DPP 4 inhibitors decrease the acitivity of the enzyme dipeptidyl peptidase by greater than 80% for up to 24 hours, thereby augmenting the meal related circulating concentrations of both GLP-1 and GIP.19The duration of effect of GLP 1 is thereby increased, thus resulting in a reduction in hepatic glucose output and increase in insulin production.

Diabetes is a chronic disease that severely effects the lives of patients suffering from it. Diabetes occurs when the body’s blood glucose levels are too high (1). There are two main types of Diabetes known as type 1 and type 2 diabetes. Type 1 diabetes occurs when the pancreas is unable to produce the adequate amounts of insulin, and patients with type 1 require daily insulin replacement in order to survive (Martini et al 2015 p. 664). Type 2 diabetes, which is the most common type of diabetes, is often correlated with obesity. The body is able to produce the normal amounts of insulin, but the tissues in the body do not respond appropriately. Type 2 diabetes can be controlled by medication and weight loss, but like type 1, it cannot be cured

The development of insulin analogues is always attempting to alleviate some of the defects of traditional insulin (Danne et al., 2002). Insulins lispro, glulisine, and aspart have a faster onset of action and shorter duration that makes them more suitable for blousing at meal times and for short-term correction of hyperglycemia (See the graph above). They are also more appropriate for using with insulin pumps. Intermediate-acting insulin (detemir) is of a similar profile of action to isophane but it is more pharmacologically predictable and is less likely to cause weight gain, whereas glargine is of a relatively flat profile of action, lasting some 18-26 hours. Despite their obvious advantages, compared with traditional insulins, no evidence

The amino acid sequence of the IAPP, more particularly the amino and carboxyl terminals, are highly conserved. This suggests that these conserved termini play an important role in its physiological function. It has been proposed that IAPP inhibits insulin secretion, delays gastric emptying, reduced appetite, suppresses glucagon release and tumorigenesis. Still, the exact role of IAPP, its functions, dysfunctions in T2D is yet to be fully understood.

Pharmacological interventions used to improve glucose control include both oral glucose lowering agents and injectables including glucose like peptide & insulin. Apart from insulin the choice of available pharmacological interventions to treat diabetics has expanded rapidly over the past decade. Till date, the efficacy & safety of these therapies have not been well documented in people with diabetics & CKD.