The Role of DPP-4 Inhibitors in the Management of Type 2 Diabetes

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Dipeptidyl peptidase-4 (DPP-4) inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral medications used to treat type 2 diabetes. They work by inhibiting the enzyme dipeptidyl peptidase-4, which is responsible for breaking down and inactivating a group of hormones called incretins. Incretins, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), play an important role in regulating blood sugar levels by stimulating insulin secretion in response to food intake and suppressing glucagon release.

Mechanism of action

DPP-4 inhibitors work by:

1. Increasing insulin secretion: By preventing the degradation of incretins such as GLP-1 and GIP, DPP-4 inhibitors help to maintain higher levels of these hormones in the blood. This, in turn, increases insulin secretion from the pancreatic beta cells in a glucose-dependent manner, meaning that insulin is only released when blood sugar levels are elevated.
2. Decreasing glucagon production: Incretins also help to inhibit glucagon secretion from the pancreatic alpha cells. Glucagon is a hormone that promotes the release of glucose from the liver, raising blood sugar levels. By reducing glucagon secretion, DPP-4 inhibitors help to prevent excessive glucose production by the liver.

These combined effects lead to better blood sugar control in people with type 2 diabetes.

Common DPP-4 inhibitors

Some examples of DPP-4 inhibitors include:

• Sitagliptin (Januvia)
• Saxagliptin (Onglyza)
• Linagliptin (Tradjenta)
• Alogliptin (Nesina)

Side effects

DPP-4 inhibitors are generally well-tolerated, with fewer side effects compared to some other diabetes medications. The most common side effects include mild gastrointestinal issues such as nausea, diarrhea, and stomach pain. In rare cases, DPP-4 inhibitors can cause more severe side effects, like acute pancreatitis, severe joint pain, and allergic reactions. It is important to discuss any concerns or side effects with your healthcare provider.

Usage with other medications

DPP-4 inhibitors can be used alone or in combination with other diabetes medications, such as metformin, sulfonylureas, or insulin. Your healthcare provider will determine the most appropriate treatment plan based on your specific medical history and blood sugar control needs.

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Topic Highlights:-

• Incretins are gastrointestinal hormones that are beneficial in the control of diabetes. They increase the amount of insulin released from the pancreas upon ingestion of food. They also inhibit glucagon release.
• DPP-4 is an enzyme that inactivates these hormones which prolongs the life of the gut hormones, and thereby controls diabetes.
• DPP-4 inhibitors act by delaying the degradation of vital gastrointestinal hormones that trigger pancreatic insulin secretion, at the same time suppressing glucagon secretion.
• DPP-4 inhibitors are significantly more efficacious in the control of the disease than commonly prescribed anti-diabetic drugs.
• This visual presentations talks about type 2 diabetes and the potential benefit of DPP-4 inhibitors in its treatment.

Transcript:-
The human pancreas contains more than a million Islets of Langerhans in varying size, scattered throughout but most profusely in its tail. They comprise about 1% of the pancreatic mass. Of the typical cell types numbering about a thousand in these islets, ß-cells make up about 80% and ß-cells making up most of the remaining. Insulin that exerts critical control over carbohydrate, fat and protein metabolism is produced in these ß-cells while the Alpha-cells secrete glucagons.

There is a close correlation between glucose metabolism and insulin secretion. Insulin secretion is released directly into the portal vein and responds precisely to small changes in glucose concentration. Glucose levels in normal individuals are in the range of 70 to 150 mg/dL. The release of insulin from ß-cells is not only due to the metabolic signals initiated by physiologic levels of glucose, the secretion is also regulated and significantly enhanced by other physiologic signals by amino acids and gut hormones during ingestion of food.

Type 2 Diabetes (Diabetes Mellitus) occurs as a result of metabolic dysfunction. Peripheral insulin resistance in skeletal muscle and adipose tissue, and impaired pancreatic ß-cell function, combination of which leads to elevated plasma glucose levels characterizes type 2 diabetes.

Inception of hyperglycemia caused by a deficiency in insulin secretion is usually the first symptom of type 2 diabetes. This is often seen in conjunction with conditions such as dyslipidemia, abnormalities in carbohydrates, fat, and protein metabolism, resulting in weight gain, and an elevation in blood pressure. Type 2 Diabetes therefore, is most frequently associated with obesity, elevated plasma free fatty acids, triglycerides, and intracellular lipid deposition.

Over time these dysfunctions can cause irreversible damage to the kidneys, eyes, heart, blood vessels, and nerves. This damage can lead to blindness, vascular clotting, myocardial infarction, stroke, amputation and even death. Many of the current therapies fail to tackle the underlying pathophysiology of diabetes, and are consequently ineffective at restoring normal control of glucose metabolism. Ultimately they do not impact the disease’s progression rate.

The body’s glucose absorption is accomplished by insulin produced in the ß-cells in the pancreatic islets of Langerhans. The gradual development of insulin resistance and the resulting impaired glucose tolerance leads to type 2 diabetes. Initially, the islets are able to respond to the increased demand of insulin secretion to maintain the normoglycemia. As the disease progresses however, increased demand of both the synthesis and secretion of insulin ultimately leads to ß-cell dysfunction.

Insulin response to glucose is amplified when delivered orally as opposed to glucose administered intravenously. Peptide hormones called incretins are released from the intestine that enhances insulin secretion from the pancreas. Investigations have shown that incretins play multiple roles in metabolic homeostasis following nutrient absorption. They enhance glucose-stimulated insulin secretion from the pancreas as well as regulate the rate of delivery of nutrients such as glucose into circulation.

Incretins produced in small glands in the intestinal wall, called the crypts of Lieberkühn (these glands are present in the mucous membrane open into the intestine) and the pancreas, regulate the rate at which nutrients transit the gastrointestinal tract and thereby regulate the rate of delivery of nutrients such as glucose into circulation. The incretins have a powerful effect on gastrointestinal motility, particularly gastric emptying, thereby decreasing the rate of glucose absorption after a carbohydrate-rich meal. In the brain, GLP-1 decreases food and fluid intake. Leptin-induced appetite suppression is in part mediated by GLP-1.

The incretin effect is blunted in individuals with type 2 diabetes, and this appears to contribute to glucose intolerance. The incretin defects in patients with type 2 diabetes are due to impaired secretion of insulin, accelerated metabolism of the incretin hormones, and the effect of the hormones being compromised.

The two predominant incretins areglucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP).

Glucose-dependent insulinotropic peptide (GIP), also known as gastric inhibitory polypeptide, is a 42 amino acid peptide hormone synthesized in and secreted from K-cells in the intestinal epithelium, the majority of which are located in the proximal duodenum. GIP secretion is primarily regulated by nutrients, especially fats. Although the primary action of GIP is the stimulation of glucose-dependent insulin secretion, the physiological significance of GIP action in the adipocyte is less well defined.

Glucagon-like peptide GLP-1 is produced in enteroendocrine L-cells in the distal ileum and colon in response to oral intake of nutrients. Basal plasma levels of intact GLP-1 in humans is 5–10 picomols or pM and can increase to approximately 50 pM postprandially. This secretion is regulated by several intracellular signals. Experiments have demonstrated that the secretion is controlled by nutrients, neural and endocrine factors. The first phase of GLP-1 release is observed within 10 to 15 minutes, and direct nutrient contact induces the second phase of the secretion in 30 to 60 minutes. The vagus nerve plays an important role in mediating the rapid release of this hormone from the L-cells in response to nutrient ingestion. The neuropeptide GRP stimulates GLP-1secretion in humans.

GLP-1 is secreted from intestinal endocrine cells in two principal molecular forms, as GLP-1 (7-36) amide and GLP-1 (7-37). Studies have shown that postprandial levels of GLP-1 are significantly decreased in diabetic patients. The impaired secretion is a consequence rather than a cause of diabetes.

These peptides stimulate insulin secretion, and, unlike other insulinotropic agents, they do so in a glucose-dependent manner. While the insulinotropic action of GLP-1 is especially well preserved, the exogenous GIP is comparatively less effective than GLP-1 at stimulating insulin secretion in type 2 diabetics. Also, no correlations between metabolic parameters and GIP responses have been established in type 2 diabetes patients.

However, significant impairment of the secretion of GLP-1 has been observed in type 2 diabetes patients, and, the impairment was found to be related to impaired ß-cell function.

Research has shown that removal of the first six amino acids results in a shorter version of the GLP-1 molecule with substantially enhanced biological activity. The majority of circulating biologically active GLP-1 is found in the GLP-1(7-36) amide form. The structure of GLP-1 (as also GIP and GLP-2) reveals a highly conserved alanine at position two, rendering this peptide ideal putative substrate for the aminopeptidase, dipeptidyl peptidase-IV (DPP-IV). (The N-terminal region of GLP-1 has the second amino acid residue alanine, which makes it a prey for DPP-IV digestion.)

The postprandial release of the hormone GLP-1 from L-cells in the intestine exerts biological actions that contribute to its ability to lower glucose, including inhibition of gastric motility and gastric acid secretions thereby reducing meal-associated increases in glycemic excursion. It suppresses glucagon secretion in the pancreatic Alpha-cells and suppresses food intake in both diabetic and non-diabetic individuals by slowing down digestion and decreasing appetite.

The biological activities of GLP-1 include stimulation of glucose-dependent insulin secretion and insulin biosynthesis, inhibition of glucagon secretion and gastric emptying, and inhibition of food. The stimulatory and inhibitory effects of GLP-1 on insulin and glucagon levels, respectively, are glucose dependent. Thus GLP-1 does not stimulate insulin secretion or inhibit glucagon secretion in conditions of hypoglycemia. In animal studies it has been seen that GLP-1 induces islet cell neogenesis and proliferation.

GLP-1 has the potential to preserve or enhance ß-cell function in type 2 diabetes due to its ability to stimulate ß-cell proliferation and neogenesis and inhibit apoptosis. In the light of these beneficial actions, GLP-1 is viewed as a potential therapeutic agent for the treatment of type 2 diabetes.

The action of GLP-1 is essential for maintaining normal glucose homeostasis as disruption of their biological activity leads to impaired glucose tolerance. The major therapeutic drawback with GLP-1 is its very short half-life of less than two minutes following exogenous administration, since it is rapidly inactivated by the enzyme DPP-IV.

DPP-IV is a membrane-associated peptidase of 766 amino acids serine protease that is anchored to the surface of cells or as a circulating soluble form in plasma. It is ubiquitously expressed in increased levels in the kidney and in lesser concentration in numerous tissues including the liver, pancreas, placenta, thymus, spleen, epithelium cells, vascular endoplasm, and lymphoid and myeloid cells, and, as a soluble circulating form in plasma, adjacent to the sites of GLP-1 release.

As a membrane spanning protein, DPP-IV has two distinct mechanisms of action – intracellular signaling properties independent of its enzymatic function, and the other, in its enzymatic function, DPP-IV prefers substrates with an amino-terminal proline or alanine at position two. DPP-IV specifically cleaves dipeptides from the amino terminus of oligopeptides or proteins that contain alanine or proline in the penultimate position (it exhibits postproline or alanine peptidase activity), thereby generating biologically inactive peptides. (It works by cleaving the N-terminal region of two amino acids X-proline or X-alanine.)

Since GLP-1 has an alanine residue at position two, it is a substrate for DPP-IV. DPP-IV degrades GLP-1 by causing it to give an inactive amide. An amine at position two is absolutely essential for inhibition. GLP-1 is rapidly degraded to GLP-1-(9-36)NH2 within 30 minutes of its entering the DPP-IV containing blood vessels that drain the intestinal mucosa. The primary route for clearance of GLP-1 is the kidney.

Preventing the degradation of native GLP-1 by inhibiting the activity of the DPP-IV enzyme has emerged as a therapeutic strategy for enhancing endogenous GLP-1 action. DPP-IV inhibitors can prevent the rapid degradation of incretin hormones thereby resulting in postprandial increase in levels of biologically active and intact GLP-1.

DPP-IV inhibitors are orally administered drugs, and work by blocking GLP-1 degradation to keep its concentration for a longer period of time. Thus by enhancing endogenous incretin action, DPP-IV inhibitors are able to lower blood glucose in a glucose-dependent manner and enhance beta-cell mass by promoting proliferation, neogenesis, and survival. They also promote satiety, thereby reducing food intake and, subsequently, body weight.

Many DPP-IV inhibitors are now being examined to mitigate the progression of insulin resistance that occurs over time in diabetic patients. Several DPP-IV inhibitors such as vildagliptin, sitagliptin, and saxagliptin have been part of clinical trials. The inhibitors of DPP-IV have advantages over the GLP-1 analogs in that they are orally available and relatively free from side effects.

Selectivity, binding, pharmacokinetic profiles, drug interactions and pharmacodynamic profiles are important factors that need to be considered in choosing a suitable DPP-IV inhibitor.

Recent studies have shown that vildagliptin appears to be safe and efficacious as monotherapy in type 2 diabetic patients, particularly in those with higher baseline A1Cs. Vildagliptin may contribute to the slowing or stopping disease progression. Several clinical trials have demonstrated improved glycemic control with the addition of vildagliptin to a variety of agents, including sulfonylureas, metformin, thiazolidinediones, and insulin. Researchers believe that vildagliptin is generally safe and well tolerated, with a side-effect profile similar to that of placebo, either alone or in combination with other agents.

Sitagliptin is an orally active and selective inhibitor of the DPP-IV enzyme. Clinical data indicate that patients treated with sitagliptin for 24 weeks at doses of 100 or 200-mg a day showed reductions of HbA1c and improved beta-cell function and no change in body weight. When administered with metformin or glitazones, sitagliptin has a complementary effect. When taken with either metformin or thiazolidinediones there resulted a significant reduction in A1c and fasting glucose at 24 weeks which led to a greater proportion of patients achieving A1c less than 7% and improved beta cell function. Sitagliptin has been well tolerated by most patients. But some people have experienced adverse effects such as respiratory tract infection, diarrhea, headache and joint pain.

In October 2006 the FDA approved sitagliptin phosphate tablets for use with diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus. The tablets are available in 25-, 50-, and 100-mg strengths. Sitagliptin can be used alone or in combination with metformin or peroxisome proliferators-activated receptor gamma agonists when treatment with either drug alone provides inadequate glucose control. Other DPP inhibitors are part of clinical trials while the FDA has accepted drugs such as vildagliptin for review.