6 Pancreatic Hormones and Antidiabetic Drugs

Polypeptide hormone produced by the pancreatic beta cell

Insulin

Insulin synthesis and release are modulated by the following:

Glucose

 Amino acids, fatty acids, and ketone bodies also stimulate insulin release

 Islets of Langerhans contains several cell types, other than beta cells that help modulate insulin secretion

 a-adrenergic pathways inhibit secretion of insulin – the predominant inhibitory mechanism

 B-adrenergic stimulation – increases insulin release

 Elevated intracellular Ca2+ acts as an insulin secretagogue

 Insulin binds to the extracellular domain of specific high-affinity receptors (with tyrosine kinase activity) on the surface of liver, muscle, and fat cells.

 When insulin binds, specific tyrosine residues of the insulin receptor become phosphorylated which will lead to a signal transduction cascade.

Insulin

Actions of Insulin

 Insulin promoted systemic cellular K+ uptake

 Liver: inhibits glucose production

 Muscle: Increase glycogen deposition

Classified by the timing of its action in the body, including the onset of action and duration of action

Insulin Preparation

used to treat all manifestations of hyperglycemia in both type 1 (insulin-dependent) and type 2 (non-insulin dependent) diabetes mellitus

Insulin Preparations

INsulin Preps AEs

 hypoglycemia (symptoms include tachycardia, tremor, sweating, confusion, agitation, and in more severe cases, loss of consciousness or coma)

 Hypokalemia, hypertrophy of the SC fat at the injection site, weight gain

Insulin Prep Table

Insulin Prep Table

 These agents are modified with different amino acid residues to make them more soluble, allowing them to rapidly dissociate into monomers

 They are often injected minutes before a meal and provide better postprandial control of glucose levels than regular insulin

Rapid-acting

Regular crystalline insulin naturally self-associates into a hexameric molecule (6 insulin molecules) when injected SQ. before it is absorbed, it must dissociate to dimers and then to monomers

Short-acting

 Insulin NPH (neutral protamine Hagedorn)

 This insulin is modified with the addition of protamine, which prolongs the time required for absorption and increases the duration of action

Intermediate-acting

These agents were modified to mimic basal insulin secretion and have a steady release with no peak effect

Long-acting

Patients with type 2 DM may require higher doses of insulin, due to insulin resistance

Dosing considerations

 This may occur in patients recently diagnosed with Type 1 DM

 It occurs when beta cells in the pancreas can still secrete enough endogenous insulin to aid in blood glucose control, resulting in reduced exogenous insulin requirement

Honeymoon phase

 Oftentimes with acute illness, there is an increase in cortisol, which causes an elevation in blood glucose

 Patients with an acute illness may require higher insulin doses

Acute illness

Sulfonylureas

 1st generation: Tolbutamide, chlorpropamide, tolazamide

 2nd generation: Glyburide, glipizide, glimepiride

1st Gen Sulfonylureas

Tolbutamide, chlorpropamide, tolazamide

2nd Gen Sulfonylureas

Glyburide, glipizide, glimepiride

 All are equally effective in lowering blood glucose

1st generation: Tolbutamide, chlorpropamide, tolazamide

 2nd generation: Glyburide, glipizide, glimepiride

are prescribed more often ; they are more potent and have fewer adverse effects and drug interactions

2nd generation agents Sulfonylureas

Approved for the management of adults with Type 2 DM since they require functional pancreatic beta cells to produce their effect on blood glucose ; they cannot be used in patients with Type 1 DM

Sulfonylureas

 These agents are oral insulin secretagogues ; they cause insulin release from pancreatic beta cells

 They bind to the SUR1 (sulfonylurea receptor), and block ATP- sensitive K+ channels resulting in depolarization. The voltage gated Ca2+ channels open, resulting in Ca2+ influx and triggering the insulin release

 Long term use also reduces serum glucagon, which may contribute to hypoglycemic effects

Sulfonylureas

Sulfonylureas AEs

hypoglycemia, weight gain

Sulfonylureas Precautions

caution must be used in patients with hepatic or renal dysfunction ; caution must also be used in patients with a sulfa allergy

Meglitinides Agents

Repaglinide, Nateglinide

They are oral insulin secretagogues ; Have similar action to sulfonylureas, but they bind to distinct regions on the SUR1 molecule

Repaglinide, Nateglinide

 Approved for Type 2 DM

 Since they have fast onset and short duration of action, they are recommended in patients with irregular meal schedules and in patients who develop late postprandial hypoglycemia when taking a sulfonylurea

 They are used instead of sulfonylureas in patients with a history of sulfa allergy

Meglitinides
Repaglinide, Nateglinide

Repaglinide, Nateglinide AEs

hypoglycemia ; weight gain (Repaglinide)

Biguanides Agent

Metformin

 Indication: Type 2 DM

Biguanides

Metformin

 It reduces the hepatic glucose production and intestinal absorption of glucose; it does not alter insulin secretion. These effects are believed to be due to an increase in the activity of AMP kinase, a key intracellular regulator of energy homeostasis.

 Also increases peripheral insulin sensitivity

 Its glucose lowering action does not depend on functional pancreatic beta cells

Biguanides

Agent: Metformin

Biguanides Advantages

rarely causes hypoglycemia and weight gain

Biguanides AEs

GI distress, has potential to cause lactic acidosis (characterized by nonspecific symptoms: NV, abdominal pain, lethargy, hyperventilation, and hypotension)

Biguanides CIs

Due to an increased risk of lactic acidosis, metformin should not be used in patients with CHF, renal impairment, or who are seriously ill
 Metformin should be temporarily discontinued before iodinated contrast, due to the potential for acute kidney injury and increased risk for lactic acidosis

Thiazolidinediones Agents

Pioglitazone, Rosiglitazone

 Indications: Type 2 DM

Thiazolidinediones Agents

Pioglitazone, Rosiglitazone

 These agents are insulin sensitizers; they act to decrease insulin resistance

 They bind to a specific intracellular receptor, PPAR-y (peroxisome proliferator-activated receptor-gamma), a member of the nuclear-receptor family

Thiazolidinediones Agents

Pioglitazone, Rosiglitazone

They predominantly affect liver, skeletal muscle, and adipose tissue

Thiazolidinediones Agents

Pioglitazone, Rosiglitazone

Thiazolidinediones Agents

Pioglitazone, Rosiglitazone

IN THE LIVER

decrease glucose output and insulin levels

Thiazolidinediones Agents

Pioglitazone, Rosiglitazone

IN MUSCLEa

these agents increase glucose uptake

Thiazolidinediones Agents

Pioglitazone, Rosiglitazone

IN ADIPOSE TISSUE

these drugs increase glucose uptake and decrease fatty acid release and may increase the release of hormones such as adiponectin and resistin

The actions of these drugs require the presence of insulin

Can reduce plasma glucose and TG

Thiazolidinediones Agents

Pioglitazone, Rosiglitazone

 Indications: Type 2 DM

Thiazolidinediones Agents

Thiazolidinediones AEs

edema, weight gain

Thiazolidinediones Precautions

cause an increased risk for fractures and bladder cancer, can cause or exacerbate CHF

Thiazolidinediones CIs

heart failure, liver disease

A-Glucosidase Inhibitors Agents

Agents: Acarbose, Miglitol

 Act as competitive, reversible inhibitors of pancreatic a- amylase and intestinal a-glucosidase enzymes; they act in the lumen of the intestine

 Inhibition of a-glucosidase prolongs the digestion of carbohydrates and reduces peak plasma glucose levels

A-Glucosidase Inhibitors Agents

Agents: Acarbose, Miglitol

Indications: Type 2 DM ; helpful in reducing postprandial glucose

A-Glucosidase Inhibitors Agents

Agents: Acarbose, Miglitol

A-Glucosidase Inhibitors Agents

Agents: Acarbose, Miglitol

AEs

GI distress and flatulence

A-Glucosidase Inhibitors Agents

Agents: Acarbose, Miglitol

CIs

intestinal diseases such as intestinal obstruction & inflammatory bowel disease

 Glucagon-like Peptide-1 agonists

 GLP-1 agonists

 GLP-1 agonists AGENTS

Exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide

Type 2 DM ; also cause weight loss ; therefore, liraglutide is also approved for weight management

GLP-1 agonists

Exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide

GLP-1 agonists

Exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide

AEs

GI distress

GLP-1 agonists

Exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide

Precautions

increased risk for acute pancreatitis and thyroid tumors

 Analogs of the hormone incretin (GLP-1)

 Increase glucose-dependent insulin secretion; decrease inappropriate glucagon secretion, slow gastric emptying, decrease food intake, and promote B-cell proliferation

GLP-1 agonists

 DPP-4 inhibitors

 Dipeptidyl Peptidase 4 inhibitors

 DPP-4 inhibitors Agents

Sitagliptin, saxagliptin, linagliptin

Type 2 DM

DPP-4 inhibitors Agents

Sitagliptin, saxagliptin, linagliptin

DPP-4 inhibitors Agents

Sitagliptin, saxagliptin, linagliptin

AEs

rhinitis and URTI ; may cause pancreatitis

 DPP-4 is responsible for the proteolysis of incretins, including GLP-1 and glucose-dependent insulinotropic peptide

 These agents inhibit DPP-4 to increase active incretins. This leads to an increase in insulin synthesis and release and suppresses glucagon production in a glucose-dependent manner.

 They may also improve beta cell function

DPP-4 inhibitors Agents

Amylin Analogs Agent

Pramlintide

 Indication: used in combination with insulin for Type2 DM

Amylin Analogs Agent

Pramlintide

Amylin Analogs Agent

Pramlintide

AEs

nausea, hypoglycemia, gastroparesis

 Amylin is a polypetide stored and secreted by beta cells of the pancreas ; it is cosecreted with insulin to reduce blood sugar. Concentrations are abnormally low in patients with DM.

 Pramlintide can reduce postprandial glucose through prolongation of gastric emptying, reduction of prostprandial glucagon secretion, and reduction of caloric intake through centrally mediated appetite suppression.

 Causes weight loss and reduces postprandial glucose levels

Amylin Analogs Agent

Pramlintide

SGLT2 inhibitors

Sodium-Glucose Cotransporter 2 Inhibitors

SGLT2 inhibitors Agents

Canagliflozin, empagliflozin, dapagliflozin

Indications: Type 2 DM

SGLT2 inhibitors Agents

Canagliflozin, empagliflozin, dapagliflozin

SGLT2 inhibitors Agents

Canagliflozin, empagliflozin, dapagliflozin

Advantages

weight loss and a modest decrease in BP

SGLT2 inhibitors Agents

Canagliflozin, empagliflozin, dapagliflozin

AEs

include genitourinary infections and increased serum potassium

SGLT2 inhibitors Agents

Canagliflozin, empagliflozin, dapagliflozin

CI

severe renal impairment

 SGLT2 is the main site of filtered glucose reabsorption

 These agents inhibit SGLT2 in the proximal renal tubules; this results in reduced reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose (RTG)

 Reduction of filtered glucose reabsorption and lowering of RTG results in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations.

SGLT2 inhibitors Agents

Canagliflozin, empagliflozin, dapagliflozin

 Produced by the alpha cells of the pancreas

 Structurally similar to secretin, VIP, and gastric inhibitory peptide

Glucagon

Glucagon secrition is inhibited by

elevated plasma glucose, insulin, and somastostatin

Glucagon secrition is stimulated by by

amino acids and sympathetic stimulation and secretion

for the treatment of severe hypoglycemia ; can be used as a diagnostic aid in which it provides intestinal relaxation prior to radiologic examination

Glucagon

Glucagon AEs

: low incidence of NV

 Stimulates adenylate cyclase to produce increased cAMP

 It increases blood glucose by stimulating glycogenolysis and gluconeogenesis in the liver

 In general, its actions oppose the actions of insulin 

Large doses produce marked relaxation of the smooth muscle in the stomach, intestines and colon.

Glucagon

 Indication: for hyperinsulinemic hypoglycemia

Diazoxide

Diazoxide AEs

sodium retention, GI distress, and changes in circulating white blood cells

: this agent opens ATP-dependent potassium channels on pancreatic beta cells, resulting in inhibition of insulin release.

Diazoxide