Diabetes Mellitus

The beta cells of the pancreas

1) glucose

2) other nutrients e.g amino acids

3) other sugars e.g mannose

4) hormones

5) fatty acids

6) ketone bodies

7) autonomic neurotic stimulus

Conditions that activate alpha-2 adrenergic receptors

When taken orally than when taken I.V. this is so because of the presence of incretins in the GIT.

Incretins are a group of metabolic hormones found in the GIT that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood glucose-dependent mechanism.Some incretins (GLP-1) also inhibit glucagon release from the alpha cells of the islets of Langerhans. In addition, they slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying and may directly reduce food intake.

GLP -1( Glucagon like Peptide 1)

GIP (Glucose Dependent Insulinotropic Peptides) or GIT inhibitory peptide

It is biphasic

1) the first phase has a rapid onset of action and a short duration ( reaches it's peak in 1-2mins )

2) the second phase has a delayed onset of action and a prolonged duration

1) glucose in the blood enters the beta cells by facilitated diffusion through glucose transporters (GLUT 1-7)

Hyperglycaemia ➡️ increased intracellular ATP ➡️ closure of ATP dependent K+ channels ➡️ reduced efflux of K+ causes depolarization of beta cells ➡️ opening of Ca++ channels ➡️ increase in intracellular calcium which leads to exocytosis and release of insulin.

Insulin secretagogues

There are specialized insulin receptors found on the membrane of most tissues. These receptors consist of two covalently linked heterodimers ( alpha and beta subunits).

The action of insulin is tied to tyrosine kinase. Insulin binds to alpha subunits on the extracellular surface of the cells and then activates tyrosine kinase activity in the intracellular portion of the Beta subunits.

1) promotes storage of glucose and fat in specialized target tissues.

2) influences cell growth and metabolic function of several tissues by causing active transport of amino acids into cells.

3) it stimulates glucose uptake by tissues

4) it reduces hepatic glycogenolysis by inhibiting glycogen phosphorylase 5) it promotes hepatic glucose storage by stimulating glycogen synthetase

5) it promotes hepatic glucose storage by stimulating glycogen synthetase 6)it inhibits hepatic gluconeogenesis7) it inhibits lipolysis8) regulates gene transcription

6)it inhibits hepatic gluconeogenesis

7) it inhibits lipolysis

8) regulates gene transcription

Liver and kidney

Liver- 60%

Kidney- 35-40%

Kidney- 60%

Liver- 30-40%

3-5 minutes

1) Hyperglycemia

2) abnormal metabolism of carbohydrates, lipids and proteins

3) increased risk of complications due to vascular disease

Hyperglycemia

It creates a high osmotic pressure which damages blood vessels causing microvascular complications like retinopathy and nephropathy and macrovascular complications like atherosclerosis.

1) Type 1

2) type 2

3) gestational DM

4) DM due to other causes

Juvenile onset DM or Insulin dependent DM

there is total destruction of Beta cells leading to absolute/total insulin deficiency. I.e there is no insulin produced in the body.

Either:

1) there is insulin resistance (i.e the body develops a resistance to insulin produced) leading to relative insulin deficiency

2) insulin secretory defect (the beta cells cannot secrete enough insulin)

Starts with pregnancy. May or may not end after pregnancy

1) some infections e.g cytomegalovirus

2) immune mediated diabetes and other genetic defects

3) disease of the exocrine pancreas

4) endocrinopathy e.g acromegaly, Cushing's syndrome and pheochromocytoma

1) glucocorticoids

2) statins

1) polyuria

2) polydipsia

3) polyphagia

4) unexplained fat loss

1) the fasting blood glucose level test

2) oral glucose tolerance test (OGTT)

3) glycated haemoglobin test

>126mg/dl

On a normal, two hours after a glucose rich meal, a person's blood sugar must have gone low to normal conditions. If after two hours, his blood glucose level is >200mg/dl, the person has diabetes.

1) glucose(endogenous and exogenous) are not utilized effectively by the organs. It only builds up in blood.

2) glucosuria - the body tries to maintain homeostasis due to the high blood sugar level by increasing excretion of glucose in urine

3) increased glucose in urine draws more water leading to polyuria (causing dehydration and polydipsia)

4) there is increased rate of nitrogen excretion due to increased protein metabolism

5) uncontrolled gluconeogenesis, converting amino acids to glucose

6) increase in lipolysis leading to formation of ketone bodies

7) the presence of excess glucose, nitrogenous bodies and ketone bodies causes osmotic diuresis leading to dehydration, abnormalities in electrolyte and acid-base balance.

1) diabetic ketoacidosis ( people with poorly managed type 1 DM are more prone to this)

2) hyperosmolar coma

Lifestyle changes ( exercise and diet)

1) insulin preparations

2) insulin secretagogues

3) Biguanide

4) Thiazolidinediones

5) alpha glucosidase inhibitors

6) incretin based therapy

7) amylin analogues

( By Thiazo, "Alpha Amy" Increased Insulin Preparations and Secretagogues)

1) rapid acting with very fast onset of action and short duration

2) short acting with rapid onset of action

3) intermediate acting

4) long acting with slow onset of action

Rapid Glu hAS a Lisp

Insulin Glulisine

Insulin aspart

Insulin lispro

Regular Insulin

NPH -Neutral Protamine Hagedom

Long acting Detamines insulin glargine

1) insulin Detamir

2) Insulin glargine

Subcutaneously

Isophane

1) as clear solutions at neutral pH

2) small amounts of zinc are added to improve stability and shelf life

1) as turbid suspensions at neutral pH

2) some contain varying concentrations of zinc in acetate buffer

It is a soluble long acting drug

To replace the normal basal and prandial insulin levels. Intermediate and long acting are given to maintain the former while rapid and short acting are help to meet meal time requirements.

1)NPH 70/ regular 30

2)NPH 50/ regular 50

3) NPL 50/ lispro 50

4) NPL 75/ lispro 25

5) NPA 70/ aspart 30

NPA-neutral Protamine aspart

NPL-neutral Protamine lispro

Because they have a rapid onset of action and an early peak(I hr). This makes them mimic normal endogenous prandial Insulin secretion. They are also suitable to take immediately before a meal.

It has a short duration of action (4-5hrs)

Regular insulin

It has a fast onset of action:effect appears within 30mins (though still slower than the rapid acting insulin). It is short acting (it reaches its peak in 2-3hrs), whereas rapid acting Insulin reaches it's peak in 1hr. It has a longer duration of action than rapid insulin (to 4-5 hours, reaches zero level at 12hrs)

Regular Insulin is a hexamer. After SC administration, the Insulin hexamer is too large and bulky to transport across the vascular endothelium into the blood stream. Thus it acts like an insulin depot taking time to dilute in the interstitial fluid as the hexamer is broken down to dimers and monomers.

Because of it's slower onset of action than rapid Insulin. if it is given at meal time, blood glucose level will rise faster than the administered insulin leading to early post prandial Hyperglycemia and an increased risk of late postprandial Hyperglycemia.

Onset of action- 2-5 hrs

Duration of action- 4-12hrs

It's action is highly unpredictable. The action depends on dose. Smaller doses give earlier but lower peak of action and shorter duration of action compared to larger doses.

Onset of action- one to one and half hours

Time to reach peak action- 4-6hrs

Maximum activity is maintained for a long time (11-24hrs)

1) hypoglycemia

2) immune reaction

3) lipodystrophy at injection site

1) malabsorption

2) flatulence

3) abdominal bloating

4) nausea

5) they don't cause hypoglycemia unless when given with other antidiabetics

DPP-4 enzymes

These are drugs that are resistant to the DPP-4 enzyme

They inhibit the DPP-4 enzymes

As subcutaneous injection

They stimulate release of insulin from the beta cells of the pancreas in the same manner that glucose does.

They bind to SUR1( sulphonyurea receptor 1) and block the beta cells' ATP sensitive potassium channels

1) they are effectively absorbed from the GIT

2) food and Hyperglycemia can reduce their absorption

3) they are largely bound to plasma proteins especially albumin

4) they are metabolized by the liver and excreted in the urine

The second generation is about 100 times more potent than the first generation. E.g Gilbenclamide is about 150 times more potent than tolbutamide.

They are used to manage Hyperglycemia in type2 DM

Patients with renal failure or deficiency

1) hypoglycemia

2) nausea

3) vomitting

4) cholestatic jaundice

5) agranulocytosis

6) adverse sensitivity reactions

7) aplastic and haemolytic anaemia

8) rashes

9) chlorpropamide causes hyponatremia

10) chlorpropamide causes alcohol induced flushing

1) the first generation have very low specificity of action

2) the first generation have delayed and unpredictable onset of action

3) the first generation have undesirable longer duration of action

4) the first generation have more side effects

5) the first generation are less potent than than the second generation

Repaglinide ( Mega Rape)

Same as sulphonyureas

Peak blood levels are obtained in 1hr and half life is in one hour

Patients with hepatic impairment( it is metabolized to inactive derivatives in the liver)

Hypoglycemia

Nateglinde (Nathan is a D )

By guanide, "formin" met "phen"

1) Metformin

2) phenformin

Phenformin

1) metphormine is an antihyperglyceamic and NOT hypoglycemic ( it is a euglyceamic agent-it maintains the normal concentration of blood glucose)

2) it does not stimulate Insulin production from the pancreas (unlike the insulin Secretagogues)

3) it does not cause hypoglycemia even in high quantities

4)it reduces hepatic glucose production by activating AMPK(AMP-activated protein kinase)

5) impairs renal gluconeogenesis

6) slows glucose absorption from the GIT

7) increases removal of glucose from the blood

8) reduces plasma glucagon levels

1) it is absorbed mainly from the small intestine

2) it does not bind to plasma proteins

3) it is excreted unchanged in urine

4) it has a half-life of 1 and half to 3 hrs

1) nausea

2) vomitting

3) diarrhoea

4) abdominal discomfort

5) anorexia

6) reduces intestinal absorption of vitamin B12

7) it also causes lactic acidosis

Increase the dose of the drug slowly and take with meals

1) Metformin+ glibenclamide

2) Metformin+ proglitazone

Rosi and Tro have gone Pro for "glitazone"

1) rosiglitazone

2) troglitazone

3) proglitazone

Acarbose

Miglitol

1) incretin mimetics

2) DPP-4 inhibitors (gliptins)

Incretin mimics EXEcutive LIRA DUe to "tides"

1) exenatide

2) liraglutide

3) dulaglutide

The DPP-4 inhibitors have 4 kids whose last name is the gliptins and first names are SITA, VILDA, SAXA and LINA

Amy "tied" Lin's Pram

1) Pramlintide

Insulin sensitizers

1) they are agonists on the Peroxisome Proliferator Receptor-gamma( PPR-gamma).

2) this receptor activates insulin responsive genes. They act as Insulin sensitizers. They increase insulin sensitivity in peripheral tissues

3) they also

a) lower hepatic glucose production

b) they enhance glucose transport into muscle and adipose tissues

1) they are absorbed within 24hrs

2) they are metabolized by the liver

Do not use if there is a hepatic defect

Fluid retention

1) alpha glucosidase enzymes are enzymes that breakdown complex carbohydrates to monosaccharides

2)these drugs thus inhibit the action of alpha glucosidase on the intestine thereby reducing intestinal absorption of starch, dextrin and disaccharides

3) the resultant effect is delayed absorption of carbohydrates and a blotting of post prandial Hyperglycemia in both normal and diabetic patients

4) they also have insulin-sparring effect because the body will not release any Insulin

It's a oligosaccharide

It is a desoxynojirimycin derivative

1) with other antidiabetic drugs

2) before the start of a meal

Vascular damage

End organ damage

A disorder when there is a problem in regulation of salt and water

A disorder of carbohydrate metabolism

Diet

Pathways through which the body produces glucose example gluconeogenesis

Insulin and glucagon

It facilitates the uptake of glucose by tissues which are not freely permeable to glucose.

90mg/dl

0-20mg/dl

75-95mg/do (85mg/dl)

The islets of Langerhans (the endocrine cells of the pancreas)

The alpha cells secrete glucagon while the beta cells secrete insulin

The acini cells

1) it is a small protein of 51 amino acids

2) it is arranged in 2 polypeptide chains , alpha and beta. The chains are connected by a disulfide bridge

what maintain the tertiary structure and biological activities

3) it has a molecular weight of 5808g/mol

1) in the pancreatic Beta cells, preproinsulin is converted to proinsulin by endopeptidases

2) the proinsulin is packaged and stored in the Golgi apparatus

3) it is then hydrolyzed to insulin and c-peptide(connecting peptide)

4) both will be released at the same time

Insulin Secretagogues are the Mega Sulphur Dephenylalanine

1) meglitinides

2) sulphonyureas

3) D-phenylalanine derivatives

TACTmide

1) tolbutamide

2) acetohexamide

3) chlorpropamide

3) tolazamide

GLI-BENPICLAME

1) Glibenclamide

2) glipizide

3) gliclazide

4) glimepiride

Orally

They stimulate release of insulin from the beta cells of the pancreas in the same manner that glucose does.

As subcutaneous injection

Orally

1) pancreatitis

2) nausea

3) vomitting

4) diarrhoea

5) slowing of the GIT

6) reaction at the injection site

7) weight loss

1) headache

Parenterally