Diabetes mellitus (DM) is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. The effects of diabetes mellitus include long term damage, dysfunction and failure of various organs.
Diabetes mellitus may present with characteristic symptoms such as thirst, polyuria, blurring of vision, and weight loss. In its most severe forms, ketoacidosis or a non ketotic hyperosmolar 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 cause pathological and functional changes may be present for a long time before the diagnosis is made.
The long term effects of diabetes mellitus include progressive development of the specific complications of retinopathy with potential blindness, nephropathy that may lead to renal failure, and/or neuropathy with risk of foot ulcers, amputation, Charcot joints, and features of autonomic dysfunction, including sexual dysfunction. People with diabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular 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 diabetes 2) Type 2 diabetes 3) Gestational diabetes
j Complications :
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 insulin production 2) Insufficient insulin action (resistant cells) - commonly detected after 40 - effects > 90% - eventually leads to -cell failure
(resulting in insulin dependence)
Gestational Diabetes
3-5% of pregnant women in the US develop gestational diabetes
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Was previously called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes. Type 1 diabetes develops when the body s immune system destroys pancreatic beta cells, the only cells in the body that make 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.
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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 diagnosed cases of diabetes. It usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. As the need for insulin rises, the pancreas gradually loses its ability to produce insulin. Type 2 diabetes is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity. African Americans, Hispanic/Latino Americans, American Indians, and some Asian Americans and Native Hawaiians or Other Pacific Islanders are at particularly high risk for type 2 diabetes. Type 2 diabetes is increasingly being diagnosed in children and adolescents.
Name
Distribution
Notes
GLUT1
GLUT2
Is widely distributed in fetal tissues. In the adult, it is expressed at highest levels in erythrocytes and also in the endothelial cells Levels in cell membranes are increased by of barrier tissues such as the blood-brain reduced glucose levels and decreased by barrier. However, it is responsible for the increased glucose levels. low-level of basal glucose uptake required to sustain respiration in all cells. 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 release of glucose during gluconeogenesis. In Is a high-capacity and low-affinity isoform 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
GLUT3
Expressed mostly in neurons (where it is believed to be the main glucose transporter isoform), and in the placenta.
GLUT4
Is the insulin-regulated glucose transporter. Found in adipose tissues and striated muscle Responsible for insulin-regulated glucose (skeletal muscle and cardiac muscle). storage.
Type 1 Typical age at onset Duration of symptoms Body weight Ketonuria Rapid death without treatment with insulin Autoantibodies Diabetic complications at diagnosis Family history of diabetes Other autoimmune disease < 40 years Weeks Normal or low Yes Yes Yes No Uncommon Common
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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 .
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A. Macrovascular compliction 1. IHD 2. CVD B. Microvascular compliction 1. Diabetic retinopathy 2. Diabetic nephropathy 3. Diabetic neuropathy 4. 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 of the patient with PDR progress to blindness in 5y time
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 of the patient with PDR progress to blindness in 5y time
Background diabetic retinopathy, showing red dots and blots (micro aneurysms and haemorrhages) and exudates.
Maculopathy in an NIDDM patient. Note the characteristic ring of leaked material (exudates) around the 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.
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Staphylococcal skin infections Retinopathy noted during a visit to the optician. Polyneuropathy causing tingling and numbness in the feet. Sexual disturbances as erectile dysfunction. Arterial disease, resulting in myocardial infarction or peripheral gangrene. Nephropathy.
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Muscle = Postprandial Hyperglycemia Fat = Increased FFA Concentration and Hepatic VLDL-TG
40% of older people are insulin resistant mostly secondary to obesity and inactivity (important in prevention and 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
Oral Glucose Tolerance Test (OGTT) *tested for 2 hrs after glucoserich drink *140-199 mg/dl signals prediabetes *>200 mg/dl signals diabetes
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.
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.
Pancreatic Hormones
Insulin-Banting and Best B cells of pancreatic islets- single chain precursor 110 amino acids- preproinsulin Cleavage -24 aa Nterminal peptideproinsulin Proteolysis- 4 aa & C peptide-insulin insulin - 51 aa- A (21 aa)& B (30aa)chains Stored in granules crystal form- 2 Zn and 6 insulin
Discovered in 1921 by Banting and Best Consist of A & B chains linked by 2 disulfide bonds (plus additional disulfide in A)
A chain
Insulin is a small protein consisting of an A chain of 21 amino acids linked by two disulfide (SS) bridges to a B chain of 30 amino acids.
Beta cells have channels in their plasma membrane that serve as glucose detectors. Beta cells secrete insulin in response to a rising level of circulating glucose.
B chain
Produced within the pancreas by cells islets of Langerhans 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 granules
Zn
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.
Glucose more than 70 mg/dl insulin secretion Glucose cells-GLUT 2 transportermetabolism-g6p pyruvate + ATP inhibits ATP sensitive K channelsdepolarization-opens voltage dependent ca channels- ca influx stimulates insulin secretion
Liver-60% Kidney 35-40% Insulin treated diabetics ratio reversed Half- life : 3-5 mins
Carbohydrate metabolism Liver : glycogenolysis,gluconeogenesis glycogenesis Muscle : glycolysis Adipose : synthesis glucose uptake, glycogenesis, glucose uptake, triglycerides
Protein metabolism Liver : protein breakdown oxidation of aa Muscles : protein synthesis increased aa uptake
Fat metabolism Liver : lipogenesis Adipose : fatty acid synthesis TGL formation lipolysis
-Tyrosine Kinase receptors are the locks in which the insulin key fits - Involved in signal transduction (insulin hormone being 1st messenger)
It stimulates skeletal muscle fibers. It stimulates liver cells. It acts on fat cells It inhibits production of certain enzyme. In each case, insulin triggers these effects by binding to the insulin receptor.
protein synthesis
glucose uptake
glycogen synthesis
fat synthesis
enzyme production
glycogen breaking
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.ht ml
The insulin receptor (IR) is a transmembrane glycoprotein, composed of 2 and 2 domains. . Its intracellular tyrosine kinase domain is activated by binding of insulin, leading to a cascade of signaling events.
Type 2 diabetes is frequently associated with obesity. Serum insulin levels are normal or elevated, so this is a disease of insulin resistance. A number of treatment options may be employed.
Short-term use:
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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, severe hypertriglyceridaemia) If targets have not been reached after optimal dose of combination therapy or BIDS, consider change to multi-dose insulin therapy. When initiating this,insulin secretagogues should be stopped and insulin sensitisers e.g. Metformin or TZDs, can be continued.
Long-term use:
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The majority of patients will require more than one daily injection if good glycaemic control is to be achieved. However, a once-daily injection of an intermediate acting preparation may be effectively used in 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 are given 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 given at bedtime, may be used, particularly when strict glycaemic control is mandatory.
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Type I (insulin dependent) diabetes patients whose body produces no insulin. Type 2 diabetes patients that do not always produce enough insulin.
Treatment
subcutaneous injection
Stage 2 Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version.
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).
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.
Types of insulin
Regular insulins:
Human insulin: Humulin (from E.coli), Novalin (from yeast) NPH - neutral protamine Hagedorn (NPH), protamine mixed. Lente insulin / Ultralente insullinzinc added
Types of insulin
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)
B- chain Position
B28 Pro
B29 Lys
Aspartic Lys acid Lys Lys Pro Pro Pro Glu Lys Lys
rapid-acting
Arg
long-acting
Insulin syringe: disposable s.c extrafine multiple use Biodegradable microspheres : insulin into polymer biodegradable microspheres-encapsulate lectin in glucose permeable membrane Inhaled insulins : aerosolised trials Others : closed loop artificial pancreas islets/pancreatic transplant gene therapy
Insulin syringe: disposable s.c extrafine multiple use Biodegradable microspheres : insulin into polymer biodegradable microspheres-encapsulate lectin in glucose permeable membrane Inhaled insulins : aerosolised trials Others : closed loop artificial pancreas islets/pancreatic transplant gene therapy
A.
Portable pen injectors Cartridges insulin & replaceable needles Multiple s.c inj Disposable insulin pens Reg insulin,lispro,aspart,gl ulisine,glargine,detem ir,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 setabdomen,flanks,thighs -change 2-3 days
Intensive insulin therapy Type 1 & some type 2 Increased requirement obesity,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 therapy Type 2 Slicing-scale regimens : 1 several inj/day Intermediate /long acting (fix)or short/rapid acting (vary) or premixed plasma glucose
B blockers: prolong hypoglycaemia Thiazides,corticosteroids ,furosemide,oral contraceptive,ca channel blockers,salbutamol : raise blood sugar, reduce insulin effect Alcohol : ppt hypoglycaemia (by depleting hepatic glycogen) Salicylates,lithium,theop hylline : enhance insulin secretion & peri glucose utilization
Diabetic mellitus : IDDM NIDDM not controlled diet and exercise failure oral hypoglycaemic underweight trauma,surgery,pregnancy Test completeness of vagotomy (no inc gastric acid secretion) Cyclic vomiting in kids,hyperemesis gravidarum,anorexia nervosa and cachexia,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
Hyperosmolar hyperglycaemic syndrome 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
Severe: unconscious/stupor 20-50 ml 50% glucose sol i.v 2-3 mins 1mg glucagon s.c/i.m - conscious 15 mins If stuporous -Honey/syrup buccal pouch
Insulin allergy 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 resistance Circulating ig G anti insulin ab neutralize insulin action in insulin treated patients Assoc autoimmune (sle) Acute : infection,trauma,surgery,drugscs,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 be started but long acting Sulphonylureas are to be avoided. Renal function should be monitored. Oral anti-diabetic agent s are not recommended for diabetes in pregnancy Oral anti-diabetic agents are usually not the first line therapy in diabetes diagnosed during stress, such as infections. Insulin therapy is recommended for both the above Targets for control are applicable for all age groups. However, in patients with 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 should be given to allow achievement of steady state blood glucose control
6 Classes :
Sulfonylureas Biguanides Sulfonylureas and biguanide combination drugs Thiazolidinediones Alpha-glycosidase inhibitors Meglitinides
bind to protein
1st generation
2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole (IPTD) was used in treatment of typhoid fever in 1940 s hypoglycemia Currently > 12,000
Rel. Potency
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)
*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 insulin release,auto off mechanism)
R R N R N R N N R N R R
Metformin is a widely used monotherapy, and also used in combination with the sulfonylureas in treatment of type 2 diabetes
- mechanism improves insulin sensitivity by increasing peripheral glucose uptake and utilization. - Zhou et al (2001) showed that metformin stimulates the hepatic enzyme AMP-activated protein kinase 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
NH
&
O S
NH O O H N N N H + N H H H N
&
O O NH
HCl
Pioglitazone
- Actos, Avandia
O S NH
O 5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione
- 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
- upon activation of this nuclear receptor by a ligand such as a TZD, PPAR 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
PPAR -
AGI s
- Precose (acarbose), - Glyset (miglitol)
H O H O N O H
H 1-(2-Hydroxy-ethyl)-2-hydroxymethylpiperidine-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, auto off 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 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 What Rx is not used in liver dz? Glipizide b/c 90% metabolized by liver
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: 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 lipid metabolism Result? A. Incr glycolysis B. Decr gluconeogenesis Advantage, disadvantage: Incr HDL, incr LDL
Rxs to elevate blood glucose: What Rx is normally released from alpha cells of pancreas in response to low blood sugar? Glucagon stimulates gluconeogenesis & glycogenolysis Uses: A. Decr GI motility for radiological exams B. Tx severe hypoglycemia C. Tx OD of beta-blocker What Rx is also used to tx hypertensive emergencies? Diazoxide mech?
Prevents closing of K+ channels in beta cells K+ efflux hyperpol
Animal insulin- atrophy s.c fatty tissue at inj site Now human and analog insulins neutral ph inj into atrophy site restores normal contours Hypertrophy of s.c fatty tissue inj Liposuction & avoid same site
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