Pancreatic hormones

Dr.HazarDr.Hazar

Pancreatic Hormones Pancreatic Hormones

Insulin AmylinGlucagon Somatostatin Pancreatic Polypeptide

The bulk of the pancreas is an exocrine gland secreting pancreatic fluid into the duodenum after a meal.

Inside the pancreas are millions of clusters of cells called islets of Langerhans. The islets are endocrine tissue containing four types of cells. In order of abundance, they are:

1.beta cells, which secrete insulin and amylin;

2.alpha cells, which secrete glucagon; 3.delta cells, which secrete somatostatin4.gamma cells, which secrete a

polypeptide.

InsulinInsulinDiscovered in 1921 by Discovered in 1921 by Banting and BestBanting and Best

Consist of Consist of AA & & BB chains chains linked by 2 disulfide bonds linked by 2 disulfide bonds

(plus additional disulfide in (plus additional disulfide in A)A)~ ~ ~ ~ A = 21amino acids B = 30 amino acids

InsulinInsulin(synthesis, storage, secretion(synthesis, storage, secretion))

Produced within the pancreas by Produced within the pancreas by ββ cells cells islets of Langerhans islets of Langerhansinsulin mRNA is translated as a single chain precursor called preproinsulininsulin mRNA is translated as a single chain precursor called preproinsulinremoval of signal peptide (which is a a part of the preproinsulin) during insertion into the endoplasmic reticulum generates proinsulinremoval of signal peptide (which is a a part of the preproinsulin) during insertion into the endoplasmic reticulum generates proinsulinWithin the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulinWithin the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin

Stored as Stored as ββ granules granules

This light micrograph of a section of the human pancreas shows one of the islets of Langerhans, center, a group of modified glandular cells. These cells secrete insulin, a hormone that helps the body metabolize sugars, fats, and starches. The blue and white lines in the islets of Langerhans are blood vessels that carry the insulin to the rest of the body.

Zn

•The main factor controlling the synthesis and secretion of insulin is the blood glucose concentration.• B cells respond both to the absolute glucose concentration and to the rate of change of blood glucose. •Other physiological stimuli to insulin release include amino acids (particularly arginine and leucine), fatty acids, the parasympathetic nervous system and incretins .The main incretins are GLP-1 and GIP which are GIT hormones.•GIP, gastric inhibitory peptide; GLP-1, glucagon-like peptide-1.

Release of insulin from β cells of Islets of Langerhans. Glucose enter β cells Via Glut2→glucokinase &Glycolysis → ↑ATP → blocks ATP sensitive K+ channel →membrane Depolarization opens a voltage-gated calcium channel and results in calcium influx and the release of preformed insulin..

GIP, gastric inhibitory peptide; GIT, gastrointestinal tract; GLP-1, glucagon-like

peptide-1.

Question for student

Suppose you have 10gm glucose I.V or 10gm oral glucose .Which one causes greater insulin release? Why?

Release of insulin from β cells of Islets of Langerhans

Stimulants ex. glucose,ACTH,a.a….

Inhibitory ex. Somatostatines….

Innervations.

Cholinergic &Noradrenergic innervations causes:

→↑insulin secretion by

vagal stim , β2-adren.agonist, Cholin agonist

→ ↓ insulin secretion by sympath.stim.,direct acting α2-adrenoceptors agonist.

InsulinInsulin(Biochemical Role(Biochemical Role))

-Tyrosine Kinase receptorsreceptors are the locks in which the insulin key fits- Involved in signal transduction(insulin hormone being 1st messenger)

The insulin receptor is a tyrosine kinase. In other words, it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins. Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity, thereby generating a biological response

Several intracellular proteins have been identified as phosphorylation substrates for the insulin receptor the best-studied of which is insulin receptor substrate 1 , the or IRS-1. When IRS-1 is activated by phosphorylation, a lot of things happen. Among other things, IRS-1 serves as a type of docking center for recruitment and activation of other enzymes that ultimately mediate insulin's effects

Pharmacological action of insulin

1.CHO

2.Fat.

3.Protein.

4.Long term effects.

Insulin↓BGL byInsulin facilitates entry of glucose into muscle, adipose &The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters. In many tissues - muscle being a prime example - the major transporter used for uptake of glucose - GLUT4 .It should be noted here that there are some tissues that do not require insulin for efficient uptake of glucose: important examples are brain and the liver. This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent.

The effects of insulin on carbohydrate, fat and protein metabolism in liver, muscle and adipose tissue

Metabolism Liver cells Fat cell Muscle CHO ↓Gluconeogenesis ↑Glu uptake ↑Glu uptake ↓Glycogenolysis ↑Glycerol syn ↑Glycolysis ↑ Glycogenesis ↑Glycogenesis   ↑Glycolysis   Fat ↑Lipogenesis ↑Syn of trigly  ↓Lipolysis ↑Fatty acid synthesis    ↓Lipolysis Protein ↓Protein breakdown ↑aauptake    ↑Protein synthesis

Endocrine pancreas and blood glucose

Islets of Langerhans secrete insulin from B- (or β-) cells, glucagon from A-cells and somatostatin from D-cells. Many factors stimulate insulin secretion, but the main one is blood glucose . Insulin has essential metabolic actions as a fuel-storage hormone and also affects cell growth and differentiation. It decreases blood glucose by: – increasing glucose uptake into muscle and fat via

Glut-4 – increasing glycogenesis – decreasing gluconeogenesis – decreasing glycogen breakdown.

Actions of InsulinActions of Insulin

Glucose transport into muscle & fat cells.Glucose transport into muscle & fat cells.Increased glycogenesis.Increased glycogenesis.Inhibition of gluconeogenesis.Inhibition of gluconeogenesis.Inhibition of lipolysis & increased formation Inhibition of lipolysis & increased formation of triglycerides.of triglycerides.Stimulation of membrane-bound energy-Stimulation of membrane-bound energy-dependent ion transporters (e.g. Na/K dependent ion transporters (e.g. Na/K ATPase).ATPase).Stimulation of cell growthStimulation of cell growth

The longer-term actions of insulin

entail effects on DNA and RNA, mediated partly at least by the Ras signalling complex. Ras is a protein that regulates cell growth and cycles between an active GTP-bound form and an inactive GDP-bound form . Insulin shifts the equilibrium in favour of the active form and initiates a phosphorylation cascade that results in activation of mitogen-activated protein kinase (MAP kinase), which in turn activates several nuclear transcription factors leading to the expression of genes that are involved both with cell growth and with intermediary metabolism. Regulation of the rate of mRNA transcription by insulin provides an important means of modulating enzyme activity. Insulin growth factor (IGF) can also bind to and activate insulin receptors

Diabetes Mellitus

Definition

Diabetes mellitus is a syndrome of disordered metabolism of CHO, lipid & protein with inappropriate hyperglycemia due to either to an absolute/partial deficiency of insulin secretion or a reduction in the effectiveness of insulin or both.

Reg. hormone.. Insulin. Counter reg. hormones ex glucagon

Classification

Diabetes mellitus is classified into 1-Type 1 Insulin dependent diabetes mellitus IDDM 2-Type 2 Non Insulin dependent diabetes mellitus NIDDM.3-Type 3 D.M.: refers to other specific causes of elevated blood glucose:a. Non-pancreatic diseases ;acromegaly, Cushing Syndrome.b.Drug therapy ; glucocorticoids, thiazides, phenytoin, diazoxide, clozapine.

Type 4 D.M.: Gestational D.M

Abnormality in glucose levels noted for the first time during pregnancy. During pregnancy, the placenta and placental hormones create an insulin resistance that is most pronounced in the last trimester.

Characteristics of Type 1 & Type Characteristics of Type 1 & Type 2 Diabetes Mellitus2 Diabetes Mellitus

Type 1 Type 2

Age of onset Usually < 25 years Usually > 40 yearsAcuteness of onset Usually sudden Usually gradualPresenting features Polyuria, polydipsia, Often asymptomatic

polyphagia, acidosisBody habitus Often thin Usually overweightControl of diabetes Difficult EasyKetoacidosis Frequent Seldom, unless under stressInsulin requirement Always Often unnecessaryControl by oral agents Never FrequentControl by diet alone Never FrequentComplications Frequent Frequent

Complications of Diabetes Mellitus:

Most of complications due to D.M. are chronic and referred as microangiopathies (affecting small blood vessels in eye, kidney, periphery…etc). These complications include:

1- Eye: retinopathy, cataract and glaucoma.2- Kidney: nephropathy and chronic renal failure.3- Nerves: neuropathy (autonomic, sensory and motor).4- Macrovascular: coronary artery disease, peripheral

vascular diseases and cerebrovascular strokes.5- Gastroparesis (weak gastric motility → delayed

gastric emptying).6- Sexual dysfunction (Impotence).

Pathophysiology

1. hyperglycemia.

2. Glucoseuria.

3. Odema &electrolyte imbalance.

4. Retinopathy.

5. Ketoacidosis.

6. Coma & death.

Clinical uses of insulin

Patients with type 1 diabetes require long-term maintenance treatment with insulin. An intermediate-acting preparation (e.g. isophane insulin, to provide a low background level) is often combined with a short-acting preparation (e.g. soluble insulin) taken before meals. Soluble insulin is used (intravenously) in emergency treatment of hyperglycaemic diabetic emergencies (e.g. diabetic ketoacidosis). Many patients with type 2 diabetes ultimately require insulin treatment.

Short-term treatment of patients with type 2 diabetes or impaired glucose tolerance during intercurrent events (e.g. operations, infections, myocardial infarction). During pregnancy, for gestational diabetes not controlled by diet alone. Emergency treatment of hyperkalaemia: insulin is given with glucose to lower extracellular K+ via redistribution into cells.

Clinical Uses of insulin

1.Diabetes mellitus: Type 1 (IDDM)2. Type 2 (NIDDM) not adequately controlled by oral-antidiabetics, during infection, surgery pregnancy.3.To reduce hyperkalemia due to renal failure

(with glucose).4- Diabetic ketoacidosis (soluble insulin)

Stage 1 Insulin was extracted from the glands of cows and pigs. (1920s)

Stage 2 Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version.

Insulin drug evolution

Stage 3 Stage 3 Insert the human Insert the human insulin insulin gene into E. coli and gene into E. coli and cultureculture the the recombinantrecombinant E.coliE.coli to produce insulinto produce insulin (trade name = Humulin(trade name = Humulin®®). ). Yeast is also used Yeast is also used to produce to produce insulin insulin (trade name =(trade name =

NovolinNovolin®®) (1987).) (1987).

Recombinant DNA technology has also made it possible to manufacture slightly-modified forms of human insulin that work faster (Humalog® and NovoLog®) or slower (Lantus®) than regular human insulin.

Human insulin is made by recombinant DNA technology. For routine use it is given subcutaneously (by intravenous infusion in emergencies). Different formulations of insulin differ in their duration of action: fast- and short-acting soluble insulin: peak action after subcutaneous dose 2-4 hours and duration 6-8 hours; it can be given intravenously

intermediate-acting insulin (e.g. isophane insulin can be mixed with soluble insulin) long-acting forms, e.g. insulin zinc suspension (crystals). The main unwanted effect is hypoglycaemia. Altering the amino acid sequence ('designer' insulins, e.g. lispro and glargine) can usefully alter insulin kinetics

Insulin Prep.

They are divided into short, intermediate & long-acting preparations:

Short-acting: – Neutral/soluble insulin

Ex. Actrapid®HM, Humulin R®

– Insulin LisproEx. Humalog®

– Insulin AspartEx. NovoRapid®

Intermediate-acting:– Isophane insulin

Ex. Protaphane®HM, Humulin N®– Insulin zinc suspension (amorphous)

Ex. Monotard®, Humulin L®

Insulin (Cont’d)

Insulin (Cont’d)

Long-acting:– Crystalline insulin zinc suspemsion

Ex. Ultratard®HM– Insulin glargine– Insulin determin

Mixed Insulins:

1.Biphasic isophane insulin30% soluble insulin/70% isophane insulin

20% soluble insulin/80% isophane insulin

2.Biphasic Insulin LisproInsulin Lispro

3.Biphasic Insulin Insulin Aspart

Insulin (Cont’d)

Side effects :Complications of Insulin Therapy1. HYPOGLYCAEMIA:

Hypoglycemic reactions are the most common complications of insulin therapy. Causes of insulin induced hypoglycemiaToo much insulin : Wrong over-dose.Too little food : delayed, missed or inadequate mealsToo much exercise : this increases glucose uptake into muscle.Clinical features of hypoglycemiaSympath: Sweating, tremor, tachycardia, pallor,Para Sympath :hunger, nauseaweakness, irritability, confusion, blurred vision and diplopia, convulsions and finally coma.

Management of hypoglycemia:

Mild episodes, where the patient is conscious, cooperative and able to able to swallow safely, are treated with oral glucose, orange juice or any sugar containing beverage or food.

Severe hypoglycemia, where the patient is unconscious or stuporous is treated

with:· Glucose, 50 ml of 50% solution I.V. OR· Glucagon, 1 mg I.M or S.C.

2- Lipoatrophy or Lipohypertrophy at injection site.

3- Insulin allergy; Local allergic reactions at injection site can cause local itching and inflammation. Systemic allergic reactions, including generalized urticaria and evenanaphylactic reactions, mediated by IgE antibodies, are rare.

4. Immune insulin resistance: A low titer of circulating IgG anti-insulin antibodies (ab) that neutralize the action of insulin to a negligible extent develops in most insulin-treated patients. Rarely, the titer of insulin ab leads to insulin resistance and may be associated with other systemic autoimmune processes ex. lupus erythematosus.

Glucagon

 Glucagon has a major role in maintaining normal concentrations of glucose in blood, and is often described as having the opposite effect of insulin. That is, glucagon has the effect of increasing blood glucose levels.

Glucagon

is a fuel-mobilising hormone, stimulating gluconeogenesis and glycogenolysis, also lipolysis and proteolysis. It increases blood sugar and also increases the force of contraction of the heart.

Physiological and pharmacological effects of Glucagon

1. Glucagon stimulates breakdown of glycogen stored

in the liver i.e increase glycogenolysis2. Glucagon activates hepatic gluconeogenesis.3.Glucagon inhibits glycolysis.4.Glucagon inhibits glycogen synthesis & glucose

oxidation.5. +ve inotropric.6. Stim. insulin release

Clinical uses of Glucagon

Glucagon can be used I.M,I.V or S.C . Treatment of hypoglycaemia in unconscious patients

(who cannot drink); unlike intravenous glucose it can be administered by non-medical personnel (e.g. spouses or ambulance crew). It is also useful if there is difficulty in obtaining intravenous access.

Treatment of acute cardiac failure precipitated by injudicious use of β-adrenoceptor antagonists where it will increase the force of contraction of the heart (positive inotropic action).

Clinical uses of Glucagon

1.Acute hypoglycemia -IM,IV,SC.

2. Acute cardiac failure ppt by β-adr.antagonists.

Treatment of chronic hypoglycemia:

By Diazoxide

in either islet tumor/ hyperplasia of the islet cells.

Acts by +ATP-sensitive k-chnnls.

Oral Antidiabetics

Sulfonylureas

Biguanides

Sulfonylureas and biguanide combinations

Thiazolidinediones

Alpha-glucosidase inhibitors

Meglitinides

Incretin mimetics and related drugsIncretin mimetics and related drugs

6 Classes :

Sulfonylureas

Block the ATP-dependent K channel in beta-cell by binding to high affinity sulfonylurea sp. Receptors w.r.present on the ATP-dependent K channel This is followed by the depolarisation of the cell membrane followed by the openning of the Ca channel. The latter is the stimulus of insulin release

Sulphonylureas

Act mainly by augmenting insulin secretionMay also increase tissue response to insulin↓serum glucagon conc.↓glucose abs.in GIT.Effective only when some residual pancreatic beta-cell activity is presentConsidered for patients who are not overweight, or in whom Metformin (Glucophage®) is contraindicated or not tolerated

Short-acting:– Tolbutamide: 0.5-1.5 g daily in divided doses, with

or immediately after breakfast; Max: 2 g daily– Gliclazide (Diamicron®): 40-160 mg daily in

divided doses, with breakfast; Max: 320 mg daily

Intermediate-acting:– Glipizide (Minidiab®): 2.5-15 mg daily in divided

doses, before breakfast; Max: 20 mg daily

Sulphonylureas (Cont‘d)Sulphonylureas (Cont‘d)

Long-acting:– Chlorpropamide (Diabinese®): 250 mg

daily with breakfast; Max: 500 mg– Glibenclamide (Daonil®): 5 mg daily with

or immediately after breakfast; Max: 15 mg daily

– Glimepiride (Amaryl®): 1-4 mg daily shortly before or with first main meal; Max: 4 mg daily

Sulphonylureas (Cont‘d)Sulphonylureas (Cont‘d)

SulphonylureasFirst-generation:1. Tolbutamide2. Acetohexamide3. Tolazamide4. Chlorpropamide

Second-generation:1. Glibenclamide (Daonil)2. Glipizide(Minidiab)3. Gliclazide (Diamicron)

Third-generation:1 .Glimepiride.2.Gliquidone.

Contraindications:– Severe hepatic and renal impairment – Breast-feeding and pregnancy– Elderly (Chlorpropamide , glibenclamide)

Adverse effects:– Nausea, vomiting, diarrhoea &constipation– Increased appetite and weight gain– Hypoglycaemia– Hypersensitivity

Sulphonylureas (Cont‘d)

- Hematological reactions: agranulocytosis (bone marrow depression), aplastic & haemolytic anaemias.

- chlorpropamide may lead to Disulfiram like action (alcohol intolerance) &

dilutional hyponatremia.

-Sudden death due to acute myocardial infarction especially with first

generation drugs

Drug interactions:

1- Drugs that AUGMENT the hypoglycaemic effect of sulphonylureas :Sulfonamides, salicylates , phenylbutazone, fibrates , dicoumarol , propranolol,MAO inhibitors , allopurinol, probenecid.

2- Drugs that DECREASE the action of sulphonylureas:Thiazides, corticosteroids, oral contraceptives

Biguanides

Metformin (Glucophage®) is the only available biguanide

Is antihyperglycemic, not hypoglycemic

Recommended for obese or insulin resistant diabetic patients

Pharmacological actions

1. Reduction of hepatic glucoeneogenesis.2. Decreased glucose absorption from the intestine.3. Increased glucose uptake skeletal muscle4. Enhancement of anaerobic glycolysis in peripheral tissue, with increased glucose removal from blood.5. Reduction of plasma glucagon level.

Metformin:– 500 mg bd-tid; Max: 3 g, usually limit to 2 g daily

Contraindications:– Hepatic or renal impairment (must withdraw)– Ketoacidosis– Predisposition to lactic acidosis: severe

dehydration, which is most likely to occur in patients with renal impairment

Biguanides (Cont’d)

Contraindications (Cont’d):– Infection, shock, trauma, heart failure,

respiratory failure, recent myocardial infarction, severe peripheral vascular disease

– Hepatic impairment, alcohol dependency– Pregnancy and breast-feeding

Biguanides (Cont’d)

Biguanides (Cont’d))

Adverse effects:– Decreased appetite– Nausea, vomiting and diarrhoea– Lactic acidosis (rarely)

– Decreased absorption of vitamin B12 and folic acid

– Allergic skin reaction – Induce ovulation in premenopausal

anovulatory women.

Sulfonylurea & Biguanide Sulfonylurea & Biguanide Combo drugs/ CocktailsCombo drugs/ Cocktails

GlucovanceGlucovance®® (Glyburide & Metformine HCl) (Glyburide & Metformine HCl)

NH

O

NH

SO

O

O

O

NH

Cl

1-[[ p-[ 2-( 5-chloro-o-anisamido) ethyl] phenyl] sulfonyl]-3-cyclohexylurea

N N

N

N

N

H

H

H

H H

+ HCl

&

&

Thiazolidinediones (TZD’s) : make cells more sensitive to insulin (esp. fatty

cells)Pioglitazone

rosiglitazone

- binds to and activates the gamma isoform of the peroxisome proliferator-activated receptor (PPARγ).

- PPARγ is a member of the steroid hormone nuclear receptor superfamily, and is found in adipose tissue, cardiac and skeletal muscle, liver and placenta

PPAR - γ

- upon activation of this nuclear receptor by a ligand such as a TZD, PPARγ–ligand complex binds to a specific region of DNA and thereby regulates the transcription of many genes involved in glucose and fatty acid metabolism.

- Marketed in USA in August of 1999

Thiazolidinediones

Also known as Glitazones

Reduce peripheral insulin resistance by enhancing uptake of glucose by skeletal muscle cells

Rosiglitazone (Avandia®): – 4 mg daily in combination with metformin or a

sulphonylurea; Max: 8 mg daily when with metformin

Pioglitazone (Actos®): – 15-30 mg daily

Contraindications:– Hepatic impairment– History of heart failure, combination of insulin– Pregnancy and breast-feeding

Thiazolidinediones (Cont’d)

Adverse effects:Adverse effects:– GI disturbances, headache, anemiaGI disturbances, headache, anemia– Weight gain & Oedema due to water retension.Weight gain & Oedema due to water retension.– Hypoglycaemia (less common for Pioglitazone)Hypoglycaemia (less common for Pioglitazone)– Liver dysfunctions ;Liver dysfunctions ;hepatic toxicity (rare)(rare)– Induce ovulation in premenopausal anovulatory

women

Thiazolidinediones (Cont’d)

GlitinidesGlitinides : : Stimulate more insulin production Stimulate more insulin production ; dependant upon level of glucose present; dependant upon level of glucose present

glitinidesglitinides

- Prandin - Prandin ® (repaglinide)® (repaglinide)

- Starlix ® (nateglinide)- Starlix ® (nateglinide)

O

OHO

NH

N

O

2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid

O

OH

NH

O

2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid

Glitinides

Stimulate insulin release byStimulate insulin release by

They are insulin secretagouges similar to sulphonylureas but with shorter

duration. Nateglinide is a benzoic acid derivative which stimulates insulin

release by blocking ATP sensitive K+ channels.

Selctive on β cells > vascular smooth muscle.

Rapid onset of action & short duration

Taken shortly before meals

Repaglinide (Repaglinide (NovoNormNovoNorm®): ®): – 500 mcg – 4 mg daily within 30 min before 500 mcg – 4 mg daily within 30 min before

main meals; Max: 16 mg dailymain meals; Max: 16 mg daily

Nateglinide: Nateglinide: – 60 mg tid within 30 min before main meals; 60 mg tid within 30 min before main meals;

Max: 180 mg tid Max: 180 mg tid

Glitinides (Cont’d)Glitinides (Cont’d)

Contraindications:Contraindications:– KetoacidosisKetoacidosis– Pregnancy and breast-feedingPregnancy and breast-feeding– Severe hepatic impairment (for repaglinide) Severe hepatic impairment (for repaglinide)

Glitinides (Cont’d)Glitinides (Cont’d)

Glitinides (Cont’d)Glitinides (Cont’d)

Adverse effects:Adverse effects:– HypoglycaemiaHypoglycaemia– Hypersensitivity reactions including pruritus, Hypersensitivity reactions including pruritus,

rashes and urticariarashes and urticaria– Abdominal pain, diarrhoea, constipation, Abdominal pain, diarrhoea, constipation,

nausea and vomiting (repaglinide)nausea and vomiting (repaglinide)

alert:alert:– Administration must always be associated Administration must always be associated

with mealswith meals

ΑΑlpha – glucosidase inhibitorslpha – glucosidase inhibitors : :Block enzymes that help digest starches Block enzymes that help digest starches

slowing the rise in B.G.L.slowing the rise in B.G.L.

AGI’sAGI’s- Precose - Precose ®® (acarbose) (acarbose), ,

- Glyset ® (miglitol)- Glyset ® (miglitol)

N

OO

OO

O

H

H H

H H

1-(2-Hydroxy-ethyl)-2-hydroxymethyl-piperidine-3,4,5-triol

Alpha glucosidase inhibitorAlpha glucosidase inhibitor

Delay the digestion & absorption of starch Delay the digestion & absorption of starch & sucrose by inhibition of intestinal alpha & sucrose by inhibition of intestinal alpha glucosidase in the intestineglucosidase in the intestine

Acarbose (Acarbose (GlucobayGlucobay®)®)– 50-100 mg tid; Max: 200 mg tid 50-100 mg tid; Max: 200 mg tid

Contraindications:Contraindications:– Pregnancy and breast-feedingPregnancy and breast-feeding– Inflammatory or malabsorptive intestinal Inflammatory or malabsorptive intestinal

disordersdisorders– Hepatic impairmentHepatic impairment– Severe renal impairmentSevere renal impairment

Alpha glucosidase inhibitor Alpha glucosidase inhibitor (Cont’d)(Cont’d)

Alpha glucosidase inhibitor (Cont’d)Alpha glucosidase inhibitor (Cont’d)

Adverse effects:Adverse effects:– Flatulence, soft stools, diarrhoea, abdominal Flatulence, soft stools, diarrhoea, abdominal

distention and paindistention and pain– Liver dysfunctionLiver dysfunction

Exenatide is a synthetic version of exendin-4, a peptide found in the saliva of the Gila monster (a lizard, which presumably evolved this as means to disable its prey by rendering them hypoglycaemic).

Incretin mimetics and related drugs

Exenatide mimics the effects of GLP-1 ,but Exenatide mimics the effects of GLP-1 ,but is longer acting. It lowers blood glucose is longer acting. It lowers blood glucose after a meal by increasing insulin after a meal by increasing insulin secretion, suppressing glucagon secretion secretion, suppressing glucagon secretion and slowing gastric emptying .and slowing gastric emptying .

It reduces food intake (by an effect on It reduces food intake (by an effect on satiety) and is associated with modest satiety) and is associated with modest weight loss. It reduces hepatic fat weight loss. It reduces hepatic fat accumulation. drugs). accumulation. drugs).

It is much more stable than GLP-1, and is It is much more stable than GLP-1, and is administered twice daily before the first administered twice daily before the first and last meal of the day. A long-acting and last meal of the day. A long-acting preparation (for once-weekly preparation (for once-weekly administration) is under investigation administration) is under investigation (Drucker et al., 2008). It can cause (Drucker et al., 2008). It can cause hypoglycaemia and a range of hypoglycaemia and a range of gastrointestinal effects. Pancreatitis is a gastrointestinal effects. Pancreatitis is a rare but sometimes severe problem.rare but sometimes severe problem.

Exenatide is not absorbed by the gut and Exenatide is not absorbed by the gut and is administered subcutaneously. Exenatide is administered subcutaneously. Exenatide is used in patients with type 2 diabetes in is used in patients with type 2 diabetes in combination with metformin with or without combination with metformin with or without a sulfonylurea when these have been a sulfonylurea when these have been inadequate.inadequate.

Gliptins

Gliptins (e.g. Gliptins (e.g. sitagliptin, vildagliptin) are ) are synthetic drugs that competitively inhibit synthetic drugs that competitively inhibit dipeptidylpeptidase-4 (DPP-4) (an enzyme dipeptidylpeptidase-4 (DPP-4) (an enzyme responsible for the degradation of the responsible for the degradation of the endogenous incretins), thereby lowering blood endogenous incretins), thereby lowering blood glucose by potentiating endogenous incretins glucose by potentiating endogenous incretins (GLP-1 and GIP)(GLP-1 and GIP)

Sitagliptin does not cause weight loss or weight Sitagliptin does not cause weight loss or weight gaingain

Sitagliptin is well absorbed from the gut and is is well absorbed from the gut and is administered once daily by mouth. It is mainly administered once daily by mouth. It is mainly eliminated by renal excretion and is also eliminated by renal excretion and is also metabolised by hepatic CYP enzymes. It is metabolised by hepatic CYP enzymes. It is well tolerated with an adverse effect profile in well tolerated with an adverse effect profile in clinical trials similar to placebo, and similar clinical trials similar to placebo, and similar occurrence of hypoglycaemia between placebo occurrence of hypoglycaemia between placebo and sitagliptin. Sitagliptin is used for type 2 and sitagliptin. Sitagliptin is used for type 2 diabetes, usually in addition to other oral diabetes, usually in addition to other oral hypoglycaemic drugs hypoglycaemic drugs

Vildagliptin is not available in the USA, is not available in the USA, where the Food and Drug Administration where the Food and Drug Administration has required further investigation to has required further investigation to exclude skin and renal toxicity.exclude skin and renal toxicity.

Potential new antidiabetics

1. Selective β3 agonist.

2. Gene therapy.

3. Β cells implants.

4. Designer insulin.

Several agents are currently being studied, including α2-adrenoceptor antagonists and inhibitors of fatty acid oxidation. Lipolysis in fat cells is controlled by adrenoceptors of the β3 subtype . The possibility of using selective β3 agonists, currently in development, in the treatment of obese patients with type 2 diabetes is being investigated

There is interest in inhibitors of protein kinase C, for example ruboxistaurin , an inhibitor specific for the β isoform of PKC, because of evidence implicating activation of this pathway in the development of vascular diabetic complications