The Pancreas and The Pancreas and Glucose HomeostasisGlucose Homeostasis

Diabetes mellitusDiabetes mellitusDM is characterized by elevated blood sugar

levels due to absolute or relative lack of insulin.

Type 1 diabetes - β-cell failure at outset◦ Insulin dependent

Type 2 diabetes - Gradual β-cell deterioration◦Early stages: Diet and Oral agents ◦Late-stage: Insulin therapy

Glycosylated hemoglobin Hb-A1c It is used to monitor the plasma glucose

concentration over prolonged periods of time (4-6 weeks).

Insulin secretion is promoted by: ◦↑ blood glucose levels

◦↑ amino acids◦ GI hormones ◦ β-2 agonist: stimulates

glycogenolysis release of glucagon

Beta cells Peripheral tissues

InsulinInsulin Insulin is a storage hormone:

i. it promotes anabolismii. inhibits catabolism of carbohydrates, fatty

acids and protein.

In the absence of insulin:i. most tissues cannot use glucose ii. fats/proteins are broken down to provide

energy.

Mechanism of action:

Insulin binds to insulin receptors on the plasma membrane and activates tyrosine kinase – primarily in adipose tissue, liver and skeletal muscle.

Liver: 1. Insulin increase the storage of glucose as

glycogen in the liver. ◦ It inserts the GLUT-2 glucose transport molecule in

the cell membrane. 1. It inhibits gluconeogenesis – thus significantly

↓ glucose output by the liver.2. It decrease the protein catabolism.

Muscle : 1. Insulin stimulates the glycogen synthesis

and protein synthesis.◦ Glucose transport into the cells is facilitated by

GLUT-4 into the cell membrane.1. It inhibits the protein catabolism.

Signs and symptomsThe classic symptoms of untreated diabetes are

loss of weight, polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).[11] Symptoms may develop rapidly (weeks or months) in type 1 diabetes, while they usually develop much more slowly and may be subtle or absent in type 2 diabetes.

Prolonged high blood glucose can cause glucose absorption in the lens of the eye, which leads to changes in its shape, resulting in vision changes. Blurred vision is a common complaint leading to a diabetes diagnosis. A number of skin rashes that can occur in diabetes are collectively known as diabetic dermadromes.

Diabetic emergencies

People (usually with type 1 diabetes) may also present with diabetic ketoacidosis, a state of metabolic dysregulation characterized by the smell of acetone, a rapid, deep breathing known as Kussmaul breathing, nausea, vomiting and abdominal pain, and altered states of consciousness.

Complicationstypically develop after many years (10–

20). damage to blood vessels. Diabetes doubles the risk of

cardiovascular disease, ”macrovascular" diseases, (related to atherosclerosis of larger arteries) include ischemic heart disease (angina and myocardial infarction), stroke and peripheral vascular disease.

Diabetes also damages the capillaries (causes microangiopathy). Diabetic retinopathy, which affects blood vessel formation in the retina of the eye, can lead to visual symptoms, reduced vision, and potentially blindness.

Diabetic nephropathy, the impact of diabetes on the kidneys, can lead to scarring changes in the kidney tissue, loss of small or progressively larger amounts of protein in the urine, and eventually chronic kidney disease requiring dialysis.

Diabetic neuropathy is the impact of diabetes on the nervous system, most commonly causing numbness, tingling and pain in the feet and also increasing the risk of skin damage due to altered sensation. Together with vascular disease in the legs, neuropathy contributes to the risk of diabetes-related foot problems (such as diabetic foot ulcers) that can be difficult to treat and occasionally require amputation.

Insulin Insulin

Adipose tissue :1. Insulin facilitates the storage of

triglyceride by: i. activating plasma lipoprotein lipaseii. inhibiting intracellular lipolysis.

2. It increase the glucose uptake by GLUT-4 insertion into the cell membrane.

Effect of insulin on glucose uptake and Effect of insulin on glucose uptake and metabolismmetabolism

glycolysisglycolysis

Insulin is a 51 AA peptideNot active orally.Insulin is inactivated by insulinase (insulin

transhydrogenase ) found mainly in liver and kidney.

Dose reduced in renal insufficiencySources of Insulin :

◦ Beef pancreas / Pork pancreas ◦ Human insulin: recombinant DNA origin

Human Insulin: Do not contain measurable amounts of

proinsulin or contaminants.Diminished antibodyLess allergic reactionsLess lipodystrophyPreferred in gestational diabetes

Insulin preparations:

A.Rapid acting insulin: Lispro, Aspart and Glulisine

B.Short acting insulin: Regular (crystalline)C. Intermediate acting insulin: NPH (isophane) and Lente (insulin zinc)

D. Long acting insulin: Protamine—zinc , Ultralente, Detimir and Glargine

Insulin Duration Route Features

LisproRapid acting

3 – 5 hrs I.V or S.C Onset within 15 minutes

Regular (crystalline)Short acting

7 – 10 hrs I.V or S.C common

NPH (Neutral protamine hagedorn)Intermediate acting

16 – 20 hrs S.C NPH can mix with regular

UltralenteLong acting

24 – 30 hrs S.C Basal level

Adverse effects of Insulin Hypoglycemia Allergic reactionsLipodystrophyOthers includes

◦ Seizures◦ Coma

HypoglycemiaHypoglycemia

Examples of four regimens that provide both prandial and basal insulin replacement. B = breakfast;L = lunch; S = supper. NPH = neutral protamine Hagedorn.

Insulin Delivery SystemsInsulin Delivery Systems

Exubera

Inhaled

Oral Anti-diabetic drugsOral Anti-diabetic drugs

Mechanisms to reduce blood sugar 1.Stimulation of pancreatic insulin release –

Sulfonylureas, Meglitinide2.Reduce the bio-synthesis of glucose in liver –

Biguanides (Metformin)3.Increase the sensitivity of target cells to insulin

-- Thiazolidinediones4.Retard the absorption of sugars from the GI

tract – Acarbose, Miglitol

Duration of action of some oral hypoglycemic agents.

Major actions of the principal oral antidiabetic drugs used to treat type 2 diabetes

A.A. Alpha-Glucosidase Inhibitors:Alpha-Glucosidase Inhibitors:

Acarbose (Glucobay) , Miglitol (Glyset) 1. They inhibit α-glucosidase which converts

dietary starch and complex carbohydrates into simple sugars

2. It reduces absorption of glucose after meals.

The main side effects includes flatulence and diarrhea.

B.B. Insulin secretagoguesInsulin secretagogues

1.1. Sulfonylureas :Sulfonylureas :

First generation : ◦ Acetohexamide◦ Chlorpropamide◦ Tolbutamide◦ Tolazamide

Second generation : Glipizide, Glyburide more potent more efficacious fewer adverse effects.

Third generation : Glimiperide

Mechanism of Action:

1)Stimulation of insulin release from the β cells of the pancreas by blocking the ATP-sensitive K+ channels, resulting in depolarization and Ca2+ influx

2)reduction in hepatic glucose production3)increase in peripheral insulin sensitivity.

Sulfonylureas

Sulfonylureas Dose(mg)

Duration(h)

First Generation Tolbutamide (Orinase) 1000-1500 6-8

Chlorpropamide (Diabinese) 250-375 24-60

Tolazamide (Tolinase) 250-375 12-24

Second generation Glipizide (Glucotrol) 10 10-24

Glyburide (Micronase) (Glibenclamide)

5 16-24

Third generationGlimepiride (Amaryl)

1-2 24

Sulfonylureas: Adverse effects :HypoglycemiaCholestatic jaundiceWeight gainCross placenta – fetal hypoglycemia.

Chlorpropamide : ◦ It can cause water retention by ↑ release of ADH

(SIADH)◦ Disulfiram-like reaction with alcohol.

2.2. Glinides: Glinides: Repaglinide, NateglinideRepaglinide, Nateglinide

More rapidly acting insulin enhancers and shorter duration than sulfonylurea.These are insulin secretagogues that act by

blocking ATP-dependent K+ channels.This leads to increased insulin secretion by

pancreatic β-cells.Hypoglycemia is the common adverse effect.Less weight gain

Repaglinide, Nateglinide

The drug has minimal renal excretion thus useful in patients with DM and impaired renal function. 

It is designed to be taken with each meal to stimulate insulin release with meal. If a meal is skipped, so is the repaglinide.

C.C. Insulin sensitizersInsulin sensitizers

1. Biguanides (Metformin):

◦ Inhibits glucose output (gluconeogenesis).◦ It increase the sensitivity of liver and muscle to insulin.

(increase uptake of glucose)◦ Does not promote insulin secretion. ◦ It causes modest weight loss.

1. Biguanides2. Thiazolidinediones

Biguanides: Metformin (Glucophage) ◦ It does not cause hypoglycemia.

◦ It produces a significant ↓ TG and LDL, and ↑HDL.

There is a serious concern about lactic acidosis especially in patients with kidney disease.

2.2. Thiazolidinediones (glitazones) Thiazolidinediones (glitazones)

Enhance glucose and lipid metabolism through action on Peroxisome Proliferator Activated Receptor (PPAR–γ)

Enhance sensitivity to insulin in muscle and fat by increasing the GLUT 4 glucose transporters.

E.g. : Pioglitazone Actos, Rosiglitazone Avandia: EMA recommended in Sep

2010 to be suspended from the EU market due to elevated cardiovascular risks

Thiazolidinediones: Beneficial effects on serum lipid; ↓TG and

↑HDL.Troglitazone (Rezulin), was withdrawn in 1990s

from the market due to an increased incidence of drug-induced hepatitis.

The main side effect of all thiazolidinediones is water retention, leading to edema .

Adverse effects of Oral Anti-diabetic drugs

Agent Mechanism Site of action Main advantages Main side effects

Sulfonylureas

Stimulating insulin production by inhibiting the KATP channel

Pancreatic beta cells•Effective •Inexpensive

•Hypoglycemia •Weight gain

Metformin Decreases insulin resistance

Liver

•May result in mild weight loss •Does not cause hypoglycemia

•GI symptoms, including diarrhea, nausea, abdominal pain •Lactic acidosis •Metallic taste

Acarbose Reduces intestinal glucose absorption

GI tract •Low risk

•GI symptoms, including diarrhea, abdominal cramping, flatulence

Thiazolidinediones

Reduce insulin resistance by activating PPAR-γ

Fat, muscle Hepatoxicity

NEW CLASSES OF NEW CLASSES OF HYPOGLYCEMICSHYPOGLYCEMICS

• Glucagon-like peptide-1 (GLP-1)

• Gastric inhibitory peptide (GIP)

• Released from the gut

A. Incretins

• Function of incretins:

1. augment glucose-dependent insulin secretion after a meal.

2. They also slow the rate of absorption of nutrients into the blood stream by:

1. reducing gastric emptying 2. may directly reduce food intake

3. They inhibit glucagon release from the alpha cells of the Islets of Langerhans.

Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4).

GIPGLP-1

DPP-4Inactive products

Dipeptidyl peptidase 4 (DPP-4) inhibitors: SITAGLIPTIN (januvia(

Exenatide (Byetta) inj

Sitagliptin)januvia(

• GLP-1 analogs. • improves glucose-dependent insulin secretion • slows gastric emptying time• decreases food intake • decreases postprandial glucagon secretion • promotes β-cell proliferation. • Consequently, weight gain and postprandial

hyperglycemia are reduced, and HbA1c levels decline. • Exenatide is administered subcutaneously.

A.Incretin Mimetics: • Exenatide Exenatide (Byetta) (Byetta)

• Liraglutide Liraglutide (Victosa): long duration of action approved in 2010(Victosa): long duration of action approved in 2010

Exenatide : Short duration of action.

Use: as an adjunct to therapy in patients with

Type 2 diabetes who have failed to achieve adequate glycemic control on a sulfonylurea, metformin, glitazone, or combination thereof.

Adverse effects: Nausea, vomiting, and diarrhea.

B. Dipeptidyl Peptidase-IV InhibitorsB. Dipeptidyl Peptidase-IV Inhibitors

Sitagliptin (Januvia) FDA approved Oct 2006Vildagliptin (Galvus) EU Approved 2008 Saxagliptin (Onglyza) FDA Approved July 2009 Linagliptin (Tradjenta) FDA Approved May 2, 2011

Sitagliptin (Januvia)

Mechanism of action•Sitagliptin inhibits the enzyme DPP-IV, which is

responsible for the inactivation of incretin hormones.

•Prolonging the activity of incretin hormones results in increased insulin release in response to meals and a reduction in inappropriate secretion of glucagon.

•Use: – as monotherapy or in combination with a

sulfonylurea, metformin or a glitazone.

Pharmacokinetics and fate

•Well absorbed after oral administration. •Food does not affect the extent of absorption. •The majority excreted unchanged in the urine. •Dosage adjustments are recommended for

patients with renal dysfunction.

Adverse effects•Nasopharyngitis and headache.

Synthetic Amylin Analog: Synthetic Amylin Analog: Pramlintide (SYMLIN): Pramlintide (SYMLIN):

Amylin: 37-aa peptide produced by beta cells

and co-secreted with insulin.Effects:

1. Inhibits glucagon secretion 2. delay gastric emptying3. suppress appetite

•indicated as an adjunct to mealtime insulin therapy in patients with Type 1 or Type 2 diabetes.

•Effects: - delays gastric emptying - decreases postprandial glucagon secretion- improves satiety

Pramlintide (SYMLIN):

•Administration of Pramlintide:

•subcutaneous injection

•injected immediately prior to meals.

•When pramlintide is initiated, the dose of rapid- or short-acting insulin should be decreased by 50% prior to meals to avoid a risk of severe hypoglycemia.

•Adverse effects are mainly gastrointestinal and consist of nausea, anorexia, and vomiting.

Agents that increase blood glucose Agents that increase blood glucose (hyperglycemics)(hyperglycemics)

Glucagon: UsesA.first aid in cases of severe hypoglycemia when the

victim is unconscious or for other reasons cannot take glucose orally.

B.treatment of overdose with beta blockers◦ It has positive inotropic action and chronotropic

action on the heart.◦ It acts by stimulation of glucagon receptors and not

through beta 1 receptors.

Diazoxide Diazoxide is a nondiuretic thiazide that promptly

increases blood glucose levels by direct inhibition of insulin secretion.

Diazoxide is useful in cases of insulinoma or leucine-sensitive hypoglycemia.

Diazoxide may cause sodium retention, gastrointestinal irritation, and changes in circulating white blood cells.