insulin,diabetes oral hypo

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INSULIN,Diabetes,ohgs



` Diabetes mellitus (DM) is a group of diseasescharacterized by high levels of blood glucose resultingfrom defects in insulin production, insulin action, orboth.

` The term diabetes mellitus describes a metabolicdisorder of multiple aetiology characterized by chronichyperglycaemia with disturbances of carbohydrate,fat and protein metabolism resulting from defects in

insulin secretion, insulin action, or both.

` The effects of diabetes mellitus include longtermdamage, dysfunction and failure of various organs.



` Diabetes mellitus may present with characteristicsymptoms such as thirst, polyuria, blurring of vision,and weight loss.

` In its most severe forms, ketoacidosis or a nonketotichyperosmolar state may develop and lead to stupor,coma and, in absence of effective treatment, death.

` Often symptoms are not severe, or may be absent,and consequently hyperglycaemia sufficient to causepathological and functional changes may be presentfor a long time before the diagnosis is made.



` The longterm effects of diabetes mellitusinclude progressive development of the specificcomplications of retinopathy with potential

blindness, nephropathy that may lead to renalfailure, and/or neuropathy with risk of footulcers, amputation, Charcot joints, and featuresof autonomic dysfunction, including sexual

dysfunction.` People with diabetes are at increased risk of

cardiovascular, peripheral vascular andcerebrovascular disease.



Other specific types of diabetes result from

specific genetic conditions (such as

maturity-onset diabetes of youth), surgery,drugs, malnutrition, infections, and other

illnesses.

Such types of diabetes may account for 1%to 5% of all diagnosed cases of diabetes.



20.8 million in US ( 7% of population)

estimated 14.6 million diagnosed (only 2/3)

Consists of 3 types:

1) Type 1 diabetes2) Type 2 diabetes

3) Gestational diabetes

j Complications :

- Stroke

- Heart attack

- Kidney disease

- Eye Disease

- Nerve Damage



Type 1 Diabetes- cells that produce insulin are

destroyed- results in insulin dependence

- commonly detected before 30

Type 2 Diabetes- blood glucose levels rise due to

1) Lack of insulinproduction

2) Insufficient insulinaction (resistant cells)

- commonly detected after 40- effects > 90%

- eventually leads to -cell failure(resulting in insulin dependence)

Gestational Diabetes3-5% of pregnant women in the US

develop gestational diabetes



` Was previously called insulin-dependent diabetes mellitus(IDDM) or juvenile-onset diabetes.

` Type 1 diabetes develops when the bodys immune system

destroys pancreatic beta cells, the only cells in the body thatmake the hormone insulin that regulates blood glucose.

` This form of diabetes usually strikes children and young adults,although disease onset can occur at any age.

` Type 1 diabetes may account for 5% to 10% of all diagnosed

cases of diabetes.

` Risk factors for type 1 diabetes may include autoimmune,genetic, and environmental factors.



` Was previously called non-insulin-dependent diabetes mellitus(NIDDM) or adult-onset diabetes.

` Type 2 diabetes may account for about 90% to 95% of all diagnosedcases of diabetes.

` It usually begins as insulin resistance, a disorder in which the cells donot use insulin properly. As the need for insulin rises, the pancreasgradually loses its ability to produce insulin.

` Type 2 diabetes is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucosemetabolism, physical inactivity, and race/ethnicity.

` African Americans, Hispanic/Latino Americans, American Indians, andsome Asian Americans and Native Hawaiians or Other Pacific Islandersare at particularly high risk for type 2 diabetes.

` Type 2 diabetes is increasingly being diagnosed in children andadolescents.



Name Distribution Notes

GLUT1

Is widely distributed in fetal tissues. In the

adult, it is expressed at highest levels in

erythrocytes and also in the endothelial cells

of barrier tissues such as the blood-brain

barrier . However, it is responsible for thelow-level of basal glucose uptake required to

sustain respiration in all cells.

Levels in cell membranes are increased by

reduced glucose levels and decreased by

increased glucose levels.

GLUT2

Is a bidirectional transporter, allowing

glucose to flow in 2 directions. Is expressed

by renal tubular cells, small intestinal

epithelial cells, liver cells and pancreatic

cells. Bidirectionality is required in liver cells

to uptake glucose for glycolysis, and releaseof glucose during gluconeogenesis. In

pancreatic -cells, free flowing glucose is

required so that the intracellular environment

of these cells can accurately gauge the serum

glucose levels. All three monosaccharides

(glucose, galactose and fructose) are

transported from the intestinal mucosal cell

into the portal circulation by GLUT2

Is a high-capacity and low-affinity isoform

GLUT3

Expressed mostly in neurons (where it is

believed to be the main glucose transporter

isoform), and in the placenta.

Is a high-affinity isoform, allowing it to

transport even in times of low glucose

concentrations.

GLUT4

Found in adipose tissues and striated muscle

(skeletal muscle and cardiac muscle).

Is the insulin-regulated glucose transporter.

Responsible for insulin-regulated glucosestorage.



Type 1 Type 2

Typical age at onset < 40 years > 50 years

Duration of symptoms Weeks Months to years

Body weight Normal or low Obese

Ketonuria Yes No

Rapid death withouttreatment with insulin

Yes No

Autoantibodies Yes No

Diabetic complications at

diagnosis

No 25%

Family history of diabetes Uncommon Common

Other autoimmunedisease

Common Uncommon

2/18/2012 INTEGRATED HEALTH SCIENCES 12



Thirst, dry mouth .

Polyuria .

Nocturia.

Tiredness, fatigue . Recent change in weight.

Blurring of vision.

Pruritus vulvae, balanitis (genital candidiasis).

Nausea; headache.

Hyperphagia; predilection for sweet foods. Mood change, irritability, difficulty in concentrating, apathy .




Acute complication

Hypoglycemic coma Diabetic ketoacidosis

Nonketotic hyperosmolar coma



A. Macrovascular compliction1. IHD2. CVD

B. Microvascular compliction1. Diabetic retinopathy2. Diabetic nephropathy3. Diabetic neuropathy4. Diabetic foot

5. dermopathy



It is the leading cause of blindness in adult Approximately 5% of patients with diabetes

progress to sever visual acuity loss In type 1 DM after 15 y the risk of having DR 98%.1/3

macular edema 1/3 PDR In type 2 diabetes after 15 y 78% DR

10-18% of NPRDR progress to PDR ½ of the patient with PDR progress to blindness in

5y time



Cotton wool spots



NeovascularizationNeovascularization

HaemorrhagiaHaemorrhagia

FibroplasiaFibroplasia

Retinal detachmentRetinal detachment

Laser cauterizationLaser cauterization



Backgrounddiabeticretinopathy,

showing reddots and blots(microaneurysms and

haemorrhages)and exudates.



Proliferative

retinopathy.

Note theabnormal

capillaries andhaemorrhages.



Maculopathy in anNIDDM patient.

Note the

characteristic ringof leaked material(exudates) aroundthe macula region.



Occurs most commonly in type 1 DM.

Marked hyperglycemia , glucosuria , polyuria

, & dehydration.

Ketosis (-hydroxybutyrate > acetoacetate)

Ketonuria, & acetone smell from the mouth.

Kussmul respiration (Detected on

examination). Loss of consciousness, may lead to death.




Staphylococcal skin infections Retinopathy noted during a visit to the

optician.

Polyneuropathy causing tingling andnumbness in the feet.

Sexual disturbances as erectile dysfunction.

Arterial disease, resulting in myocardial

infarction or peripheral gangrene.Nephropathy.




Muscle = Postprandial

HyperglycemiaFat = Increased FFA

Concentration and Hepatic

VLDL-TG



40% of older people are insulin

resistant mostly secondary to obesityand inactivity (important in preventionand treatment)

20% of the elderly have type 2 diabetes

8.5% of all adults have type 2 diabetes 90% of diabetics are managed in

primary care



Fasting Plasma Glucose Test

(FPG) - (cheap, fast)

*fasting B.G.L. 100-125 mg/dl

signals pre-diabetes*>126 mg/dl signals diabetes

Or al Glucose Toler ance Test

(OGTT)

*tested for 2 hrs after

glucose-rich drink

*140-199 mg/dl signals pre-

diabetes

*>200 mg/dl signals diabetes

j 80 to 90 mg per 100 ml, is the normal fasting blood glucose

concentration in humans and most mammals which is

associated with very low levels of insulin secretion.

A.K.A.: Glycated Hemoglobin testsA1C



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 areendocrine tissue containing four types of cells.In order of abundance, they are:

beta cells, which secrete insulin and amylin;

alpha cells, which secrete glucagon;

delta cells, which secrete somatostatin

gamma cells, which secrete a polypeptide.



Pancreatic Hormones

Insulin Amylin Glucagon Somatostatin Pancreatic Polypeptide



Insulin-Banting and Best B cells of pancreatic

islets- single chainprecursor 110 amino

acids- pr epr oinsulin Cleavage -24 aa N-

terminal peptide-pr oinsulin

Proteolysis- 4 aa & Cpeptide-insulin

insulin - 51 aa- A (21aa)& B (30aa)chains

Stored in granules ±crystal form- 2 Zn and 6insulin



Discovered in 1921 by Bantingand Best

Consist of A & B chains linked

by 2 disulfide bonds

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



A chain

B chain

Beta cells have channels in their plasmamembrane that serve as glucose

detectors. Beta cells secrete insulin in

response to a rising level of circulating

glucose.

Insulin is a small protein consisting of an A

chain of 21 amino acids linked by two disulfide

(S²S) bridges to a B chain of 30 amino acids.



Produced within the pancreas by cells islets of Langerhans

insulin mRNA is translated as a single chainprecursor called preproinsulin

removal of signal peptide during insertioninto the endoplasmic reticulum generatesproinsulin

Within the endoplasmic reticulum,proinsulin is exposed to several specificendopeptidases which excise the Cpeptide, thereby generating the matureform of insulin

Stored as granules

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

Zn



Glucose more than 70mg/dl ± insulinsecretion

Glucose cells-GLUT 2

transporter-metabolism-g6p ±pyruvate + ATP ±inhibits ATP sensitive Kchannels-depolarization-opensvoltage dependent cachannels- ca influx ±stimulates insulin

secretion



Liver-60%

Kidney ± 35-40%

Insulin treated diabetics ± ratio reversed Half- life : 3-5 mins



Basal : 5-15micron U/ml

Peak : 60 ± 90 microns U/ml (meals)



Carbohydrate metabolismLiver :

glycogenolysis,gluconeogenesisglycogenesis

Muscle : glucose uptake, glycogenesis,glycolysis

Adipose : glucose uptake, triglyceridessynthesis



Protein metabolism

Liver : protein breakdown

oxidation of aaMuscles : protein synthesis

increased aa uptake



Fat metabolism

Liver : lipogenesis

Adipose : fatty acid synthesisTGL formation

lipolysis



-Tyrosine Kinasereceptors are the locks

in which the insulinkey fits

- Involved in signal

transduction(insulin hormone being 1st

messenger)



Insulin affects many organs:

It stimulates skeletal muscle fibers.

It stimulates liver cells.

It acts on fat cells

It inhibits production of certainenzyme.

In each case, insulin triggersthese effects by binding to theinsulin receptor.

glucose

uptake

glycogen

synthesis

pr otein

synthesis

amino acids

uptake

enzymepr oduction glycogenbr eaking

fat

synthesis



Animation showing overview of diabetes:

http://www.healthscout.com/animation/1/

34/main.html Animation showing mechanism of action

of insulin:

http://www.vivo.colostate.edu/hbooks/pat

hphys/endocrine/pancreas/insulin_phys.html



The insulin receptor (IR) isa transmembraneglycoprotein, composedof 2 and 2 domains.

.Its intracellular tyrosine

kinase domain isactivated by binding of insulin, leading to acascade of signalingevents.



Type 2 diabetes is frequently associated with

obesity. Serum insulin levels are normal orelevated, so this is a disease of insulin

resistance. A number of treatment options

may be employed.



Short-term use:` Acute illness, surgery, stress and emergencies` Pregnancy` Breast-feeding` Insulin may be used as initial therapy in type 2 diabetes` in marked hyperglycaemia` Severe metabolic decompensation (diabetic ketoacidosis,

hyperosmolar nonketotic coma, lactic acidosis, severehypertriglyceridaemia)

Long-term use:

` If targets have not been reached after optimal dose of combinationtherapy or BIDS, consider change to multi-dose insulin therapy.When initiating this,insulin secretagogues should be stopped andinsulin sensitisers e.g. Metformin or TZDs, can be continued.



` The majority of patients will require more than one daily injection if good glycaemic control is to be achieved. However, a once-dailyinjection of an intermediate acting preparation may be effectively usedin some patients.

` Twice-daily mixtures of short- and intermediate-acting insulin is a

commonly used regimen.` In some cases, a mixture of short- and intermediate-acting insulin

may be given in the morning. Further doses of short-acting insulin aregiven before lunch and the evening meal and an evening dose of intermediate-acting insulin is given at bedtime.

` Other regimens based on the same principles may be used.` A regimen of multiple injections of short-acting insulin before the main

meals, with an appropriate dose of an intermediate-acting insulin givenat bedtime, may be used, particularly when strict glycaemic control ismandatory.



Type I (insulin dependent) diabetes patients whose bodyproduces no insulin.

Type 2 diabetes patients that do not always produce enoughinsulin.

Tr eatment

subcutaneous injection



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

Stage 2 Convert pig insulin into human insulin byremoving the one amino acid that distinguishes themand replacing it with the human version.

Insulin dr ug evolution



Stage 3 Insert the humaninsulin gene into E. coli andculture the recombinant E.colito produce insulin (trade name= Humulin®). Yeast is also usedto produce insulin (trade name

=Novolin®) (1987).

Recombinant DNA technology has also made it possible tomanufacture slightly-modified forms of human insulin that

work faster (Humalog® and NovoLog®) or slower

(Lantus®) than regular human insulin.



Types of insulin

Regular insulins

Insulin analogs

Pr e-mixed insulin

Shor t peptide mimics



Regular insulins:

Human insulin: Humulin ® (from E.coli),

Novalin ® (from yeast) NPH - neutral protamine Hagedorn (NPH),

protamine mixed.

Lente ® insulin / Ultralente ® insullin-zinc added



Types of insulin

Regular insulins

Insulin analogs

Pr e-mixed insulin

Shor t peptide mimics



Insulin Analogs:

Fatty Acid Acylated insulins

Insulin Lispro (Humalog®) (1996)

Insulin Aspart (NovoLog®) (2000)

Insulin Glargine (Lantus®) (2002)

Insulin Detemir (Levemir®) (Jun.,2005)

Insulin Glulisine (Apidra®) (Jan., 2006)



Amino Acid Substitutons

A-

chain

Position

B- chain Position

Source/Type

A21 B3 B28 B29 B30 B31 AndB32

Human Asn Asn Pro Lys Thr

Aspart

Asn

Asparti

c

acid Lys Th

r

Lispro Asn Lys Pro Thr

Glulisin

e

Asn Lys Pro Glu Thr

Glargine Gly Pro Lys Thr Arg

Detemir Lys Myristic

acid

r apid-acting

long-acting



Insulin syr inge: disposable s.cextrafine ± multiple use

Biodegr adable micr ospher es : insulininto polymer biodegradablemicrospheres-encapsulate lectin inglucose permeable membrane

Inhaled insulins : aerosolised ± trials Other s : closed loop artificial pancreasislets/pancreatic transplantgene therapy



A. Por table peninjector s

Cartridges insulin &replaceable needles

Multiple s.c inj Disposable insulin

pens Reg

insulin,lispro,aspart,gl

ulisine,glargine,detemir,NPH with lispro/aspart

No syringes/bottles



Continuous subcutaneous insulin

infusion devices ( i.pumps)

Most physiological method of replacement

External loop pumps-programmed-basal

&bolus insulin replacement doses-blood

glucose self monitored results Insulin resevoir,program

chip,keypad,screen,s.c infusion set-

abdomen,flanks,thighs -change 2-3 days



Intensive insulin ther apy

Type 1 & some type 2

Increased requirementobesity,adolescence,last trimesters of

pregnancy,type 2 diabetes

Formulas :carbs in meal/snack,cureent

plasma glucose & target glucose(gms of glucose disposed by 1 u of insulin)



Conventional insulin ther apy

Type 2

Slicing-scale regimens : 1 ±several inj/day Intermediate /long acting (fix)or

short/rapid acting (vary) or premixed ±

plasma glucose



B blocker s: prolonghypoglycaemia

Thiazides,cor ticoster oids,fur osemide,or alcontr aceptive,ca channelblocker s,salbutamol :raise blood sugar, reduceinsulin effect

Alcohol : ppthypoglycaemia (bydepleting hepatic glycogen)

Salicylates,lithium,theophylline : enhance insulinsecretion & peri glucoseutilization



Diabetic mellitus : IDDMNIDDM ± not controlled diet and exercise

failure oral hypoglycaemic

underweighttrauma,surgery,pregnancy Test completeness of vagotomy (no inc

gastric acid secretion) Cyclic vomiting in kids,hyperemesis

gravidarum,anorexia nervosa andcachexia,acute alcohol intoxication

Insulin shock therapy - schizophrenia



Diabetic ketoacidosis

Type 1 ± no insulin /inadequate/interrupted

replacement, stress-sepsis or pancreatitis or

high steroid therapy Nausea,vomit,abdominal pain,kussmauls

breathing, change in mental status,inc blood

and urinary ketones and glucose Rx: Aggressive i.v hydration

regular insulin i.v 0.1 IU/kg/h stat

maintain electrolytes



Hyper osmolar hyper glycaemic syndr ome Type 2 ,inadequate oral

hydration,elderly,drugs elevate blood

glucose/cause dehydration(phenytoin,steroids,diuretics,B blockers)peritoneal and haemodialysis

profound hyperglycemias,dehydration,decling mental status, seizures

Rx: aggressive rehydration low dose insulin electrolyte homeostasis



Hypoglycaemia

etio: inadequate carb,unusual physical

excertin,large dose of insulin c/f:tachycardia,palpitations,sweating,trem

ulousness,nausea ,hunger, convulsions

and coma

Rx: simple sugar/glucose ± liquid form Mild : conscious :dextrose tab, glucose

gel, sugar beverage/food



Insulin aller gy

Immediate hypersensitivity ± local/sys

urticaria Severe - anaphylaxis

Anti insulin ig E ab ±mast cells- histamine

Etio : non insulin protein contaminants

Human and analog insulins



Immune insulin r esistance Circulating ig G anti insulin ab neutralize

insulin action in insulin treated patients Assoc autoimmune (sle) Acute : infection,trauma,surgery,drugs-

cs,ketoacidosis

Rx: high doses of regular insulin Chronic : patients rx for yrs ±pork/beef insulin

Rx: purifies newer preparations



` In elderly non-obese patients, short acting insulin secretagogues can bestarted but long acting Sulphonylureas are to be avoided. Renal functionshould be monitored.

` Oral anti-diabetic agent s are not recommended for diabetes inpregnancy

` Oral anti-diabetic agents are usually not the first line therapy in diabetesdiagnosed during stress, such as infections. Insulin therapy isrecommended for both the above

` Targets for control are applicable for all age groups. However, in patientswith co-morbidities, targets are individualized

` When indicated, start with a minimal dose of oral anti-diabetic agent,while reemphasizing diet and physical activity. An appropriate duration of time (2-16 weeks depending on agents used) between increments shouldbe given to allow achievement of steady state blood glucose control



Sulfonylureas

Biguanides Sulfonylureas and biguanide combination

drugs

Thiazolidinediones

Alpha-glycosidase inhibitors Meglitinides

6 Classes :



1st generation

(1)Orinase (tolbutamide)

(3)Tolinase (tolazamide)

(6)Diabinese (chlorpropamide)

j 2nd generation

(75)Glucotrol (glipizide)

(150)Glucotrol XL (ex. rel. glipizide)

(150)Micronase, Diabeta (glyburide)

(250)Glynase (micronized glyburide)

j 3rd generation

(350)Amaryl (glimepiride)

2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole (IPTD)was used in treatment of typhoid fever in 1940s hypoglycemia

Currently > 12,000

R e l . P o t e n c y

b i n d

t o p

r o t e i n

@ may become dislodged delayed activity

*Hydroxylation of the aromatic ring appears to be the most favored metabolic pathway*Hydroxylated derivatives have much lower hypoglycemic activity



Sulfonylureas interact with receptors on

pancreatic F-cells to block ATP-sensitive

potassium channels This, in turn, leads to opening of calcium

channels

Which leads to the production of insulin

Release somatostatin(inhibits insulinrelease,auto off mechanism)



NN

NN

N

RR R

R

RR

R

- mechanism improves insulin sensitivity by increasing peripheral glucose

uptake and utilization.

- Zhou et al (2001) showed that metformin stimulates the hepatic enzymeAMP-activated protein kinase

Mech?1. inhibits gluconeogenesis2. stimulates glycolysis3. decr LDL, incr HDL

Advantage?Does not cause wt gainS.E.?Fatal lactic acidosis, N, diarrhea, abdominal discomfort, metallic taste, anorexiaChronic use leads toDecr abs of vitamin B12

Metformin is a widely used monotherapy, and also used in combination with the sulfonylureas in

treatment of type 2 diabetes



Glucovance® (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

&

&



Pioglitazone- Actos®, Avandia®

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

- PPAR is a member of the steroid hormone nuclear receptor superfamily, and is found in adipose tissue,

cardiac and skeletal muscle, liver and placenta

PPAR -

- upon activation of this nuclear receptor by a ligand such as a TZD,

PPARligand complex binds to a specific region of DNA and thereby

regulates the transcription of many genes involved in glucose and fattyacid metabolism.

S

NH

O

O

ON

5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione

- Marketed in USA in August of 1999



AGIs- Precose ® (acarbose),

- Glyset ® (miglitol)

N

OO

O

O

O

H

H H

H H

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



Sulfonylureas: Mech? A. Block K+ channels depol Ca++ channels open

insulin (this effect is glucose dependent)

B. Release somatostatin (inhibits insulin release, autooff mech) What can happen in hepatic/renal insufficiency? Hypoglycemia b/c metabolized by liver, excreted by

kidney, therefore insufficiency accumulation hypoglycemia

Do they cross the placenta? Yes, and they are teratogenic Well absorbed orally, food decr absorption Highly protein bound, Rx interactions based on

displacement



How can sulfonylureas cause a disulfiram reaction? By inhibiting aldehyde dehydrogenase incr acetaldehyde flushing,

tachy, hyperventilation Can cause Syndrome of Inappropriate ADH secretion H2O retention,

dilutional hyponatremia

1st generation sulfonlyureas: What Rx is avoided in elderly? Chlorpropamide What Rx has metabolite more active than parent? Acetohexamide What Rx has metabolite less potent than parent? Tolazamide What Rx is safest for elderly, why? Tolbutamide shortest acting What Rx has highest incidence of disulfiram reaction & SIADH? Chlorpropamide What Rx has an incr in number of deaths from CV dz compared to insulin

or placebo? Tolbutamide

2nd generation sulfonylureas (more potent than 1st



2nd generation sulfonylureas (more potent than 1st

generation): What Rxs make Glucovance? Glyburide + metformin What Rxs make Metaglip? Glipizide + metformin What Rx is most potent and long acting?

Glimepiride What Rx is less likely to cause hypoglycemia? Glipizide b/c shortest t ½ What Rx is not used in liver dz?

Glipizide b/c 90% metabolized by liver

Biguanide:



Biguanide: What Rx is a euglycemic agent? Metformin does not stimulate insulin release or cause

hypoglycemia Mech? 1. inhibits gluconeogenesis 2. stimulates glycolysis 3. decr LDL, incr HDL Advantage? Does not cause wt gain S.E.? Fatal lactic acidosis, N, diarrhea, abdominal discomfort,

metallic taste, anorexia Chronic use leads to Decr abs of vitamin B12

Meglitinides:



Meglitinides: Mech? A. Block K+ channels depol Ca++ channels open insulin B. Release somatostatin What Rx can be taken immediately before meals? Nateglinide What Rx is taken 15-30 min before meals? Repaglinide Alpha-glucosidase inhibitors:

Acarbose, Miglitol Mech? Inhibits alpha-glucosidase slow incr in glucose after meal S.E.? Flatulence, diarrhea, abdominal cramps



Thiazolidinediones: Euglycemic agents

Monitor liver fxn, do not use of decr liver fxn Rosiglitazone, Pioglitazone Mech? Stimulate peroxisome proliferator activated

receptorc(PPAR) gamma, which regulates transcription of genes that code for enzymes in carbohydrate and lipidmetabolism

Result? A. Incr glycolysis B. Decr gluconeogenesis Advantage, disadvantage: Incr HDL, incr LDL



Animal insulin- atrophy s.c fatty tissue at

inj site

Now ±human and analog insulins neutralph ±inj into atrophy site restores normal

contours

Hypertrophy of s.c fatty tissue inj

Liposuction & avoid same site



thank you

insulin,diabetes oral hypo

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