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Transcript of Diabetes
When the volume is severely depleted, however, the body will retain water at the expense of deranging electrolyte levels.
The main effector organ for fluid homeostasis is the kidney. ADH acts by increasing water permeability in the collecting ducts and distal convoluted tubules;specifically, it acts on proteins called aquaporins and more specifically aquaporin 2 in the following cascade;
ADH (argenine vasopressin-AVP) produced in the hypothalmus and stored in the posterior pituitary.
When released, ADH binds to V2 G-protein coupled receptors within the distal convoluted tubules, increasing cyclic AMP, which couples with protein kinase A, stimulating translocation of the aquaporin 2 channel stored in the cytoplasm of the distal convoluted tubules and collecting ducts into the apical membrane.
These transcribed channels allow water into the collecting duct cells. The increase in permeability allows for reabsorption of water into the bloodstream, thus concentrating the urine Diabetes STATISTICS RESEARCH DIABETES INSIPIDUS ETIOLOGY COMPLICATIONS DIAGNOSIS PATHOGENESIS OF TYPE 2 DIABETES MELLITUS Sulfonylurea medications are categorized as either first- or second-generation.
Typically used as primary or secondary agents in the treatment of type 2 diabetes.
Sulfonylureas can be rapid-acting, intermediate-acting, or long-acting based on their onset and duration of action. SULFONYLUREA THERAPY According to The World health statistics 2012 report, released on 16th may, One in 10 adults has diabetes The International Diabetes Federation estimates that the number of diabetic patients in India more than doubled from 19 million in 1995 to 40.9 million in 2007.
It is projected to increase to 69.9 million by 2025. Currently, up to 11 per cent of India’s urban population and 3 per cent of rural population above the age of 15 have diabetes.
This means that India actually has the highest number of diabetics of any one country in the entire world. TYPES
DIABETES Type-1 Type-2 Insulin-dependent diabetes Non insulin-dependent diabetes Gestational
diabetes Other types DIABETES MELLITUS Neurogenic Nephrogenic Dipsogenic Gestational DIABETES INSIPIDUS Heterogenous metabolic disorder characterised by common feature of chronic hyperglycemia with disturbance of carbohydrates,fats and protein metabolism.
The classification of diabetes mellitus given below is an etiologic classification that is ,it is classified on the basis of causation of the disease. A DISORDER OF THE METABOLISM CAUSING EXCESSIVE THIRST AND THE PRODUCTION OF LARGE AMOUNTS OF URINE. Mellitus Symptoms of Diabetes Insipidus Excessive urination and extreme thirst (especially for cold water and sometimes ice or ice water) are typical for DI.
Its symptoms are quite similar to those of untreated diabetes mellitus, with the distinction that the urine does not contain glucose and there is no hyperglycemia (elevated blood glucose). Blurred vision is rarity. Acute Metabolic Complications Late Systemic Complications Ketoacidosis HHNS Hypoglycaemia Macrovascular disease Microangiopathy Neuropathy Retinopathy Ketoacidosis is almost exclusively a complication of DM type 1.
Severe lack of insulin causes lipolysis in the adipose tissues, resulting in release of free fatty acids into the plasma.
These free fatty acids taken up by liver are oxidised through acetyl co A to ketone bodies, .
If urinary excretion of ketone bodies is prevented due to dehydration, systemic metabolic ketoacidosis occours.
Clinically, the condition is characterised by anorexia, nausea, vomitings, deep and fast breathing, mental confusion and coma.Most patients of ketoacidosis recover. Hyperosmolar hyperglycaemic nonketotic syndrome is usually a complication of type-2 DM.
It is caused by severe dehydration resulting from sustained hyperglycaemic diuresis.
Blood sugar is extremely high and plasma osmolality is high.
Thrombotic and bleeding complications are frequent due to high viscosity of blood.
Mortality rate in this condition is high. It may result from excessive administration of insulin, missing a meal, or due to stress.
Hypoglycaemic conditions are harmful as they produce permanent brain damage, or may result in worsening of diabetic control and rebound hypoglyceamia so called somogyi's effect. Nephropathy Diabetic retinopathy is an leading cause of blindnes.
There are 2 types of lesions involving retinal vessels background and proliferative.
Besides retinopathy, diabetes also predisposes the patients to early development of cataract and glaucoma. Diabetic neuropathy may affect all parts of the nervous system but symmetric peripheral neuropathy is most characteristic.
The pathologic changes are segmental demyelination, schwann cell injury and axonal damage. Renal involvement is a common complication and aleading cause of death in diabets.
There are four types of lesions :-
Pyelonephritis is an ascending urinary tract infection that has reached the pyelum or pelvis of the kidney. One of the most consistent morphologic features of diabetes is diffuse thickening if basement membrane.
Evident in the capillaries of the skin, skeletal muscle, retina, renal glomeruli and renal medulla.However, it may also be seen in such non vascular structures as renal tubules, the bowman capsule, peripheral nerves and placenta.
Despite the increase in the thickness of basement membranes, diabetic capillaries are more leaky than normal to plasma proteins.
The microangiopathy underlies the development of diabetic nephropathy, retinopathy and some forms of neuropathy The hallmark of diabetic macrovascular disease is accelerated atherosclerosis affecting the aorta and large and medium sized arteries.
Myocardial infraction, caused by atherosclerosis of the coronary arteries is the most common cause of death in diabetics.
Gangrene of the lower extremities , as a result of advanced vascular disease, is about 100 times more common in diabetes than in the general population. Head trauma,
Inflammatory disorders of the hypothalamus and pituitary and
From surgical procedures involving the hypothalamus or pituitary.
The condition is sometimes is idiopathic. DIABETES MELLITUS Type-2 Family history of type 2 DM
History of gestational DM or delivery of baby heavier than 4 kg
Polycystic ovary disease or acanthosis nigricans
History of vascular disease Type-1 Patient must have functioning pancreatic beta cells. Thus, they are not useful for patients with type 1 diabetes.
Some individuals will not respond to initial sulfonylurea therapy, and over time, most will experience failure with this therapy as the disease progresses. First Generation Agents Original sulfonylurea agents are now known as the first-generation sulfonylureas.
Were hindered by the frequency of hypoglycemia related to therapy and high dosage requirements.
The only currently utilized first-generation sulfonylurea agent in the United States is chlorpropamide.
Discontinued Medications: Acetohexamide, Tolazamide, Tolbutamide Second Generation Agents Were developed to include a shorter duration of action and shorter half-lives, which decrease the frequency and severity of side effects related to medication therapy.
These agents are most commonly used in the treatment of type 2 diabetes today.
Medications Used: Glimepiride, Glipizide, Glyburide Potential Side Effects A hypersensitivity reaction can potentially occur with sulfonylurea therapy.
Weight gain as a result of a greater amount of circulating insulin.
Drug-drug interactions are more commonly seen with the first-generation sulfonylurea agents.
One of the primary causes for drug interactions is a competition for protein binding sites, which results in a greater amount of circulating sulfonylurea agent in the bloodstream and can increase the hypoglycemic effect.
Medications that may interact with sulfonylureas include beta blockers, corticosteroids, thiazide diuretics, cyclic antidepressants, and antifungals Type 1A DM
Immune-mediated Type 1B DM
Idiopathic DIABETES INSIPIDUS DIABETES MELLITUS Carefull history and examination document presence Polyuria
Urinalysis & microscopy together with plasma eletrolytes help exclude most of the causes of polyuria.
In a normal well hydrated subject plasma osmolality is <290 mOsml/l and osmolality is 300-450 mOsmol/l. WATER DEPRIVATION TEST Water deprivation test is needed for patients with partial avp deficiency & also to differentiate DI from primary polydipsia which is very rare in children.
Should be done in the morning under observation.
8 hours fast is enough for children
Weigh the child hourly and measure plasma & urine osmolality every 2hours.
In normal subjects plasma osmolality raises (< 300) but the urine output is reduced & its osmolality rises (800-1200) Patients with primary polydipsia start with low normal plasma osmolality (280) but urine/plasma osmolality ratio rises to >2 after dehydration.
In patients with DI the plasma but not the urine osmolality rises and U/P osmolality ratio remains < 1.5
At the end of the test, ADH is given(20 mg DDAVP INTRNASALLY OR 2 mg I.M.) and fluid intake allowed.
Concentration of the dilute urine confirms central DI and failure suggest nephrogenic causes.
Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:
Fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dl)
Plasma glucose ≥ 11.1 mmol/l (200 mg/dL) two hours after a 75 g oral glucose load as in a glucose tolerance test
Symptoms of hyperglycemia and casual plasma glucose ≥ 11.1 mmol/l (200 mg/dl)
Glycated hemoglobin (Hb A1C) ≥ 6.5%.
Diagnostic test for diabetic ketoacidosis:
Blood glucose >250mg/dl, blood pH < 7.3, blood bicarbonate < 15 meq/l. Genetic factors
The genomic region most strongly associated with other autoimmune diseases, the major histocompatibility complex (MHC), is the location of several susceptibility loci for type 1 DM Environmental factors
Extragenetic factors also may contribute. Potential triggers for immunologically mediated destruction of the beta cells include viruses (eg, enterovirus, mumps, rubella, and coxsackievirus B4), toxic chemicals, exposure to cow’s milk in infancy, and cytotoxins. The nonsulfonylurea secretagogues, more commonly known as meglitinides or glinides, are hypoglycemic agents that predominantly affect postprandial glucose levels.
There are two medications considered to be within this classification of hypoglycemic agents: repaglinide and nateglinide.
The ideal candidate for glinide therapy would have type 2 diabetes for which medical nutrition therapy and exercise has not achieved euglycemia, alone or in combination with other agents. NONSULFONYLUREA SECRETAGOGUE (GLINIDE) THERAPY Potential Side effects These medications should not be used during pregnancy, in women who are breastfeeding, or in children.
Repaglinide should be used cautiously in persons with hepatic dysfunction, and routine, close monitoring of liver function is necessary.
Individuals who are elderly, malnourished, debilitated, or have adrenal or pituitary dysfunction are particularly susceptible to hypoglycemia, the most common side effect related to this class of medication (<10%).
The key measure for preventing hypoglycemia in patients taking glinides is patient education stressing the need to omit the medication if a meal is not going to be consumed. Drug Interactions Non-steriodal anti-inflammatory drugs, coumarins, some uricosuric drugs (e.g sulfinpyrazone), alcohol, monoamine oxidase inhibitors, some antibacterial drugs and some imidazole antifungal drugs have all been reported to produce severe hypoglycaemia when given with a sulfonylurea:
Drug level and/or effect decreased by: carbamazepine, charcoal, corticosteroids, estrogens, isoniazid, nicotinic acid, nonsteroidal anti-inflammatory drugs, oral contraceptives, phenobarbital, primidone, rifampin, sympathomimetics, thiazide and other diuretics, thyroid products, urinary alkalinizers.
Drug level and/or effect increased by: beta blockers, chloramphenicol, cimetidine, delavirdine, diclofenac, fibric acid derivatives, fluconazole, gemfibrozil, ketoconazole, nicardipine, salicylates, sulfonamides, telithromycin, tricyclic antidepressants.
Agents that decrease the action fo sulfonylureas on the blood glucose include high doses of thiazide diuretics and corticosteroids. BIGUANIDE THERAPY Biguanides are popular medications in diabetes treatment.
The modern form was first introduced in Europe in the late 1950s. There is only one agent, metformin, available in this class of diabetes medications
It is an antihyperglycemic agent that lowers both basal and postprandial plasma glucose and improves glucose tolerance.
Lowers blood glucose
Metformin acts in several ways to achieve this effect, including inhibiting hepatic glucose production and intestinal absorption of glucose.
Also reduces low-density and very low-density lipopproteins (LDL and VLDL, respectively)
Has half life of about 3 hours and is excreted unchanged in urine. Potential Side effects Women who are pregnant or breastfeeding should not utilize metformin therapy.
Dose-related gastrointestinal distubrances (e.g. anorexia, diarrhoea, nausea).
Should not be given to patients with renal or hepatic disease, hypoxis pulmonary disease, heart failure or shock. Such patients are predisposed to lactic acidosis because of reduced drug elimination or reduced tissue oygenation.
Long-term use may interfere with absorption of vitamin B12. Uses Phase 4 Phase 5 Phase 1 Team Anna's Fast Phase 2 Phase 3 The fed state, occurs immediately and up to 3.9 hours after consumption of food.
Circulating glucose is predominantly from an exogenous source.
Plasma insulin levels are elevated
Glucagon levels are minimal
Triglycerides are synthesized in the liver
The brain and other glucose-dependent organs utilize some of the glucose absorbed from the intestinal tract.
Excess glucose is stored in the liver, muscle, adipose tissue, and other tissues for later use. Postabsorptive state, occurs 4 to 15.9 hours after consumption of food.Blood glucose originates from the breakdown of glycogen and hepatic gluconeogenesis.
Decrease in plasma insulin levels, and glucagon levels begin to increase.
Anabolism (energy storage) ends in this phase and catabolism (energy production) begins.
Adipocyte triglyceride begins to breakdown, and free fatty acids are released into the circulatory system for use by the liver and skeletal muscle as the primary energy source and as a substrate for gluconeogenesis. The early starvation, occurs 16 to 47.9 hours after the consumption of food.
Blood glucose is generated from hepatic gluconeogenesis and glycogenolysis.
Lactate makes up half of the gluconeogenesis substrate along with amino acids (specifically alanine) and glycerol.
The secretion of insulin is suppressed, and counter-regulatory hormone (glucagon, cortisol, growth hormone, and epinephrine) secretion is stimulated. Preliminary prolonged starvation, occurs 48 hours to 23 days after food consumption.
Blood glucose originates from hepatic and renal gluconeogenesis.
Within 60 hours of starvation, gluconeogenesis provides more than 97% of hepatic glucose output.
The secretion of insulin is distinctly diminished and counter-regulatory hormone secretion is stimulated. The secondary prolonged starvation state, occurs 24 days after food consumption.
Blood glucose during this phase originates from hepatic and renal gluconeogenesis, just as in phase 4.
Rate of glucose being utilized by the brain and the rate of gluconeogenesis diminishes. Phases of Insulin Response Therapies for Diabetes Genetic Susceptibility Concordance in identical twins 50%
Susceptibility gene on HLA region in chromosome 6 Environmental factors Viral infections
Experimental induction with chemicals
Geographic and seasonal variations
Bovine milk proteins Autoimmune factors Islet cell antibodies
CD8+ T lymphocyte-mediated selective destruction of beta cells Type 1 DM PATHOGENESIS OF TYPE 1 DIABETES MELLITUS Genetic factors Concordance in identical twins 80%
Both parents diabetic 50% risk to the child Effects of Insulin Carbohydrates Fat Protein Potassium Glucose Uptake
Glycogen Systhesis ( storage)
Conversion of Carbohydrates
to Fat (Lipogenesis) Lipolysis Amino Acid Uptake (Protein Synthesis) Potassium Uptake Into Cells Constitutional factors Obesity
Low physical activity Decreased insulin secretion Amylin
Glucose toxicity of islets
Lipotoxicity Degradation of Insulin Insulin Resistance Receptor and post receptor defects
Impaired glucose utilisation Hydrolysis of the disulfide linkage between A&B
• 60% liver, 40% kidney(endogenous insulin)
• 60% kidney,40% liver (exogenous insulin)
• Half-Life 5-7min (endogenous insulin)
Delayed-release form( injected one)
• Category B ( not teratogenic)
• Usual places for injection: upper arm, front& side
parts of the thighs& the abdomen.
• Not to inject in the same place ( rotate)
• Should be stored in refrigerator& warm up to
room temp before use.
• Must be used within 30 days. Administration: Increased hepatic glucose syntheis Subcutaneous injection
Check blood sugars regularly Refrigerate until use
Once vial is punctured, it is good for 28 days and can be left at room temperature (except for glargine which is 90 days) Storage: Hyperglycaemia Type 2 DM Insulin Types of Insulin Preparations 1. Ultra-short acting
3. Intermediate acting
4. Long-acting Insulin Synthesis, Storage, and Secretion Discovered in 1921 by Banting and Best
Consist of A & B chains linked by 2 disulfide bonds (plus additional disulfide in A)
A = 21 amino acids
B = 30 amino acids
Produced within the pancreas by cells from the islets of Langerhans on the pancreas
Insulin mRNA is translated as a single chain precursor called preproinsulin
Removal of signal peptide during insertion into the endoplasmic reticulum generates proinsulin
Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin
Stored as B granules Insulin Biochemical Role Tyrosine Kinase receptors are the locks in which the insulin key fits
Involved in signal transduction (insulin hormone being 1st messenger) Pathophysiology
Diabetes Insipidus PATHOGENESIS OF COMPLICATIONS Non-enzymatic glycosylation:- The early glycosylation produced to form irreversible advanced glycosylation end products(AGE).
The biologic effects of AGE-receptor signalling include:
1.Release of cytokines and growth factors from macrophages and mesangial cells.
2.Increased endothelial permeability
3.Increased procoagulant activity on endothelial cells and macrophages and
4.Enhanced proliferation and synthesis of extravascular matrix by fibroblasts and smooth muscle cells.
Polyol pathway mechanism:
sorbitol+ NAD fructose+NADH+H+
Excessive oxygen radicals aldol reductase sorbitol
One of the most promising therapies in the fight against diabetes is the replacement of insulin-producing cells. This cell replacement therapy includes the transplantation of islet cells provided by a donor pancreas, which can function in diabetes patients for years. Islet transplant recipients can maintain some insulin production, more easily manage their blood sugar levels, eliminate hypoglycemic episodes and experience an improved quality of life. Cell Replacement Therapy
Replacing Insulin Producing Cells
Reversing diabetes requires a 2-pronged strategy; halt autoimmunity and prevent rejection of transplanted tissue. In both cases, the body must be re-educated to tolerate insulin-producing cells.
DRI clinical trials already show that transplanting islet cells – the cells that produce insulin -- can restore insulin production. But, currently, islet transplant recipients must take powerful immunosuppressive drugs for life. These drugs often cause unwanted side effects, including damage to the islets themselves. They also shut down the patient’s entire immune system, leaving him or her susceptible to other viruses and infections.
Immune system cells
Re-educating the Immune System
Teaching the Body to Accept Insulin-Producing Cells
One of the most critical challenges we face in our commitment to cure diabetes is to develop new sources of insulin-producing cells. Donor tissue is in short supply and, as a result, we must develop alternative sources of insulin-producing cells.
At the Diabetes Research Institute, we’re actively pursuing research in the following areas:
Stem Cells & Diabetes: Scientists are trying to develop stem cells into insulin-producing islet cells. If successful, that could provide an unlimited supply of islet cells.
Transdifferentiation: Researchers have determined that adult cells, which already perform a given function, have the potential to be reprogrammed to become another cell type and take on a new function, perhaps as insulin-producing cells.
Xenotransplantation: The use of insulin-producing cells obtained from animals, such as pigs, represents an attractive alternative source of islets for transplantation.
Cell Expansion (microRNA): DRI researchers are studying microRNA molecules that regulate key, biological processes in our bodies such as cell growth and the development of stem cells into functional, adult cells. We've identified a subset of these genes that is shown to play an early, crucial role in the development and function of insulin-producing islet cells.
Cell Regeneration: There is mounting evidence the body may be able to regenerate or "regrow" insulin-producing cells through a natural, self-repairing process – even among those with type 1 diabetes.
Optimizing Cell Function: DRI researchers have identified key molecules involved in insulin release. This finding will help assess beta cell function and may also play a significant role in maintaining long-term function no matter the source of the cells. Cell Sources and Regeneration Developing an Unlimited Supply of Insulin-Producing Cells
The cause of the underlying condition should be treated when possible.
Central diabetes insipidus may be controlled with vasopressin (desmopressin, DDAVP). You take vasopressin as either a nasal spray or tablets.
Desmopressin (DDAVP) A synthetic analog is superior to native AVP because: it has longer duration of action (8-10 h vs 2-3 h) more potent.
Its antidiuretic activity is 3000 times greater than its pressor acitvity DDAVP.
Usually given intranasally but can be given orally or I.M. for comatose patients or during surgery.
DDAVP can also be used in mild haemophilla or von wilebrand disease and as treatement for nocturnal enuresis in children.
If nephrogenic DI is caused by medication (for example, lithium), stopping the medication may help restore normal kidney function. However, after many years of lithium use, the nephrogenic DI may be permanent.
Hereditary nephrogenic DI and lithium-induced nephrogenic DI are treated by drinking enough fluids to match urine output and with drugs that lower urine output. Drugs used to treat nephrogenic DI include:
Anti-inflammatory medication (indomethacin)
Diuretics [hydrochlorothiazide (HCTZ) and amiloride] TREATMENT OF DIABETES INSIPIDUS Pancreas 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:
beta cells, which secrete insulin and amylin;
alpha cells, which secrete glucagon;
delta cells, which secrete somatostatin
gamma cells, which secrete a polypeptide. Insulin Drug Evolution Stage 1 Insulin was extracted from the glands of cows and pigs. (1920s) Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version. Stage 2 Stage 3 Insert the human insulin gene into E. coli and culture the recombinant E.coli to produce insulin (trade name = Humulin®).
Yeast is also used to produce insulin (trade name = Novolin®) (1987). Thank You Nandu Vinayasri Priyanka Shruthi Sri Latha Metformin is used to treat patients with type 2 diabetes.
It does not stimulate appetite (rather the reverse) and is consequently the drug of first choice in the majority of type 2 patients who are obese and who fail treatment with diet alone.
It can be combined with sulfonylureas, glitazones or insulin.