BYTIKAL KANSARA

BARODA MEDICAL COLLEGE (BMC)

DIABETES MELLITUS

• Diabetes Mellitus (DM) refers to a group of common metabolic disorders that share the common phenotye of hyperglycemia

• Depending on etiology, factors contributing to hyperglycemia includes:– Reduced insulin secretion– Decreased glucose utilization– Increased glucose production

CLASSIFICATION• Type I DM • Type II DM• Other specific types:– Genetic deficiency of B- cell functions• Hepatocyte nuclear transcriptioon factor 4 alfa (MODY 1)• Glucokinase (MODY 2)• HNF – 1alfa (MODY 3)• Insulin promoter factor 1 (MODY 4)• HNF 1beta (MODY 5)• neuroD1 (MODY 6)

– Genetic defects in insulin action• Type A insulin resistance• Leprechaunism• Lipodystrophy syndromes

– Dieases of exocrine pancreas: pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis

– Endocrinopathies: Acromegaly, Cushing Syndrome, pheochromocytoma, hyperthyroidism

– Drug or chemical induced: pentamitice, nicotinic acid, glucocorticoids, thyroid hormones, phenytion, protease inhibitors, clozapine

– Infections: congenital rubella, CMV, Coxsachie– Uncommon forms: anti-insulin receptor antibodies– Other genetic conditions associated with Diabetes: Down

Syndrome, Klinefelter Syndrome, Turner’s Syndrome, Friedrich’s Ataxia, Huntington’s Chorea, Porphyria

– Gestational Diabetes Mellitus

SPECTRUM OF GLUCOSE HOMEOSTASIS & DM

TYPE OF DIABETES

NORMAL GLUCOSE

TOLERANCE

HYPERGLYCEMIA

PRE-DIABETES DIABETES MELLITUS

Impaired fasting glucose or

impaired glucose tolerance

Not insulin requiring

Insulin required for

control

Insulin required

for survival

TYPE 1

TYPE 2

OTHER SPECIFIC TYPESGRSTATIONAL DIABETESTIME (Years)

FPG <100 mg/dl 100-125 mg/dl 126 mg/dl

2-HR PG 140 mg/dl 140-199 mg/dl/ 200 mg/dl

NORMAL PHYSIOLOGY OF INSULIN ACTION

http://1.bp.blogspot.com/_N-RTY7s9S4A/SJwltA7yq7I/AAAAAAAAAUg/-rtv3wsulaE/s400/Insulin.jpg

RISK FACTORS FOR DIABETES MELLITUS

• Family history of diabetes (parent or sibling)• Obesity (BMI > 25)• Habitual physical inactivity• Race/ethinicity• Previously identified IFG or IGT• History of GDM or delivery of baby > 4 kg• Hypertension ( BP > 140/90 mmHg )• HDL cholestrol level < 35 mg/dl &/or a TG level > 250 mg/dl• PCOD or Acanthosis nigricans• History of vascular disease

PATHOGENESIS OF DM 1

http://www.discoverymedicine.com/Didier-Hober/files/2010/08/discovery_medicine_hober_no51_figure_5.jpg

http://ocw.tufts.edu/Content/14/lecturenotes/265878/133132_medium.jpg

http://ocw.tufts.edu/data/51/673764/674515_xlarge.jpg

http://img.medscape.com/slide/migrated/editorial/cmecircle/2001/145/prato/slide02.gif

METABOLIC ABNORMALITIES OF DM TYPE DEUX

http://4.bp.blogspot.com/_l2LRboVHKr4/TMZ9sVGyxZI/AAAAAAAAAH4/-B6JocyPDOQ/s320/xxx.....111diabetes-symptoms.jpg

MAIN INSULIN RESISTANCE SYNDROMES

• The main insulin resistance syndromes include– The Metabolic Syndrome (Syndrome X)– Polycystic Ovary Syndrome (PCOS)

METABOLIC SYNDROME

http://professional.diabetes.org/content/multimedia/images/lge/lge_qhscw16-metabolic%20syndrome-4%20copia.gif

http://kardiol.com/wp-content/uploads/2011/01/metabolic-syndrome-2.jpg

COMPLICATIONS

ACUTE

Diabetic Ketoacidosis

Hyperglycemic hyperosmolar state

CHRONIC

MicrovascularEye

disease

Neuropathy

Nephropathy

MacrovascularCoron

ary

Peripheral

Cerebrovascu

lar diease

s

Others

GI & GU

Dermatologic

Infections

Periodontal

diseases

DIABETIC KETOACIDOSISSYMPTOMS

Nausea/Vomitting Thirst/Polyuria Abdominal Pain Shortness Of Breath

PHYSICAL SIGNS Tachycardia Dehydration/Hypotension Tachpnea/Kussmaul Respiration/Respiratory Distress Abdominal Tenderness Lethargy/Obtundation/Cerebral Oedema/Possibly Coma

http://www.bestsyndication.net/images_com/2010/02_february/04/20100204_diabetic_ketoacidosis-lg01.jpg

PATHOPHYSIOLOGY OF DK

DKA HHS

GLUCOSE 250-600 600-1200

SODIUM 125-135 135-145

POTASSIUM N / Increased N

MAGNESIUM N N

CHLORINE N N

CREATININE Slightly reduced Moderately increased

OSMOLALITY 300-320 330-380

PLASMA KETONES ++++ +/-

BICARBONATE < 15 mEq/L N / Slightly reduced

ARTERIAL pH 6.3 – 7.3 > 7.3

ANION GAP Increased N / Slightly Increased

COMPARATIVE LABORATORY IN DK & HHS

http://pmj.bmj.com/content/80/943/253/F1.large.jpg

TREATMENT OF DKINITIAL EVALUATION

History & physical examinationLaboratory Tests: ABG, CBC, Urinalysis, RBS, BUN,

creatinine.ECG & CXRStart IV fluids … 1 L of 0.9% NaCl /hr initially (15 – 20

ml/kg/hr)DIAGNOSTIC CRITERIA

RBS > 250 mg/dlpH < 7.3S. bicarbonate < 15 mEq/LModerate ketonuria & ketonemia

FLUID REPLACEMENT

• 2 – 3 L of 0.9% NaCl over first 1 – 3 hrs (10-15 ml/kg/hr);

• Followed by: 0.45% NaCl @ 150 – 300 ml/hr• Change to 5% glucose & 0.45% NaCl when

glucose level reaches 250 mg/dl

SHORT ACTING INSULIN

• IV (0.1 U/kg) or IM (0.3 U/kg) stat• Then, 0.1 U/kg/hr continuous infusion;

increase to 2 to 3 times, if no response by 2 – 4 hrs

• If initial potassium < 3.3 mEq/L, do not administer insulin till potassium corrected to > 3.3 mEq/L

ELECTROLYTE CORECTIONSPOTASSIUM

10 mEq/L when K+ < 5.5 mEq/L, ECG normal, urine flow & creatinine documented;

40 – 80 mEq/L, when initial K+ < 3.5 mEq/L or bicarbonate given

BICARBONATE If pH = 6.9 – 7.0 after initial hydration, HCO3 50

mEq/L in 200 ml sterile water with 10 mEq/L KCl If pH < 6.9, 100 mEq/L HCO3 with 20 mEq/L KCl

over 2 hrs in 400 ml sterile water

• Monitor glucose, BP, pulse, respiratory rate, mental status, fluid intake & output every 1 – 4 hrs.

CHRONIC COMPLICATIONS OF DM

• MICROVASCULAR– Eye disease• Retinopathy• Macular oedema

– Neuropathy• Sensory• Motor• Autonomic

– Nephropath

• MACROVASCULAR– Coronary artery disease– Peripheral artery disease– Cerebrovascular disease

• OTHERS– Gastrointestinal– Genitourinary– Dermatologic– Infections– Cataracts– Glaucoma– Periodontal disease

MECHANISM OF COMPLICATIONS

http://img.medscape.com/fullsize/migrated/editorial/clinupdates/2001/612/delprato_02.gif

1. Advanced glycosylated end-products2. Increased metabolism by sorbitol pathway

Alters redox potential Increases cellular osmolality Generated reactive oxygen free radicals

3. Diacylglycerol activating protein kinase C4. Increases flux through hexoseamine pathway.

PROPOSED THEORIES

OPHTHALMIC COMPLICATIONS

http://images.emedicinehealth.com/images/healthwise/medical/hw/h9991431_001.jpg

TREATMENT OF OPHTHALMIC COMPLICATIONS

• Prevention• Prophylactic photocoagulation

Laser photocoagulation– Panretinal– focal

RENAL COMPLICATIONS OF DM

• Causes ESRD

http://3.bp.blogspot.com/-fMj_wJT6nfo/TaiM81DjrJI/AAAAAAAAAlI/xvtxy9ZHtRI/s1600/clip_image006.jpg

Necrotising papillitis

http://missinglink.ucsf.edu/lm/IDS_106_DM_Complications/ASSETS/DMrenalNPgross.jpg

TREATMENT OF RENAL COMPLICATIONS

• Maintain blood glucose level• Maintain BP to < 130/80 mmHg• Use ACE-I & ARBs• CCBs, B-blockers, Diuretics• Protein restriction 0.8 g/kg/day in

microalbunemia & <0.8 g/kg/day in macroalbunemia

• Renal transplantation

NEUROPATHY

http://pmj.bmj.com/content/82/964/95/F1.large.jpg

TREATMENT OF NEUROPATHY

• Improve glycemic control• Reduce chances of hypertension &

hypertriglyceridemia• Avoid smoking, alcohol• Supplement vitamins• Daily care of foot wear• For chronic painful neuropathy – use

antidepressants, anticonvulsant

GI/GU COMPLICATIONS• Delayed gastric emptying• Altered small & large bowel motility• Nocturnal diarrhoea• Oesophageal dysfunction

• Erectile dysfunction• Reduced sexual desire• Dysparenuria• Reduced vaginal lubrications• Diabetic cystopathy

TREATMENT OF GI/GU COMPLICATIONS• Small frequent meals• Metoclopromide• Domperidone• Erythromycin– Interacts eith motilin receptors

• Loperamide• Octreotide • Diabetic cystopathy – self cathaterisation• Sildenafil (Viagra) for erectile dysfunction

CARDIOVASCULAR COMPLICATIONS

• Absence of chest pain (“Silent ischemia”) is common

• One of the risk factors for atherosclerosisTREATMENT

Same as per the cardiac complication

http://wirelesshealth.files.wordpress.com/2010/12/pic2001.jpg

LOWER EXTREMITY COMPLICATIONS

http://missinglink.ucsf.edu/lm/IDS_106_DM_Complications/ASSETS/Ischemicfoot.jpg

http://www.podiatrytoday.com/files/imagecache/normal/PT07Diabetes1.png

http://www.onkocet.onkocet.eu/userfiles/image/plason_sds.jpg

DERMATOLOGIC COMPLICATIONS

http://accessmedicine.net/loadBinary.aspx?name=harr&filename=harr_c929f007t.jpg

NECROTISING LIPOIDICA

DIABETICORUM

http://accessmedicine.net/loadBinary.aspx?name=hurs13&filename=hurs13_c014f035t.jpg

NECROBIOSIS DIABETICORUM: Atrophy of skin

DIAGNOSISCRITERIA FOR DIAGNOSIS OF DIABETES MELLITUS

•Symptoms of Diabetes plus random blood glucose concentration >= 200 mg/dl or•Fasting plasma glucose >= 126 mg/dl or•Two-hour plasma glucose >= 200 mg/dl during an oral glucose tolerance test

SCREENING TESTS

• Widespread use of FPG for screening is recommended because:– Large number of people who meet the criteria are

unaware of their problem & are asymptomatic– Epidemiological studies show that type 2 DM may

be present for a decade before the diagnosis– As many as 50 % of individuals with DM have one or

more of the complications– Treatment of DM has favorably altered the natural

history of the disease

• Individuals >45 years of age are to be screened every 3 years

• Individuals who are overweight (BMI > 25) and have an additional risk factor for the disease should also be screened

LONG TERM TREATMENTTRETMENT GOALS FOR ADULTS WITH DIABETES MELLITUS

GLYCEMIC CONTROLHb A1C < 7.0

Preprandial capillary plasma glucose level

90 – 130 mg/dl

Peak postprandial capillary plasma glucose

< 180 mg/dl

BLOOD PRESSURE < 130/80 mmHg

LIPIDSLow density lipoproteins < 100 mg/dl

High density lipoproteins > 40 mg/dl

Triglycerides < 150 mg/dl

BEFORE GIVING MEDICATIONS

• Diabetic education• Nutrition (Medical Nutrition Therapy, MNT)• Exercise

PATIENT EDUCATION

• Self-monitoring of blood glucose• Urine ketone monitoring• Self insulin administration• Foot & skin care• Management of hypoglycemia

MEDICAL NUTRITION THERAPY• FATS

– 20 – 35% of total calories– Saturated fats < 7% of total calories– < 200 mg/day of dietary cholesterol– Two or more servings of fish/week– Minimal trans fats consumption

• CARBOHYDRATES– 45 - 65% of total calorie intake– Type & amount of carbohydrate is important– Sucrose containing food must be consumed with adjustments in insulin

• PROTEINS– 10 – 35% of total calorie intake

• OTHER COMPONENTS– Fibre containing food may reduce postprandial glucose excrusions– Nonnutrient sweeteners

EXERCISE

• Around 150 mins/week

ASSESSMENT OF LONG TERM GLYCEMIC CONTROL

• GLYCATED HAEMOGLOBIN (HbA1C)– Non-enzymatic glycation of hemoglobin– Keep less than 7%– That is around < 170 mg/dl– Status of around last 3 months

• FRUCTOSEAMINE ASSAY– For prior 2 weeks

• Other method is : 1,5 anhydroglucitol assay

TREATMENT OF DM

• Type I DM– Give insulin primarily

• Type II DM– Give oral hypoglycemic drugs, primarily

TREATMENT OF TYPE I DM

PREPARATION ONSET PEAK EFFECTIVE DURATION

SHORT ACTING, SC (Lispro, Aspart, Glulisine) <0.25 0.5 – 1.5 3 – 4

SHORT ACTING, SC (regular) 0.5 – 1.0 2 – 3 4 – 6

SHORT ACTING, INHALED (inhaled regular insulin) < 0.25 0.5 – 105 4 – 6

LONG ACTING (NPH, Detemir, Glargine)

1 – 4 6 – 10 10 – 16 Glargine up to 24 hrs

http://img.medscape.com/fullsize/migrated/501/976/smj501976.fig3.gif

http://dtc.ucsf.edu/images/graphs/graph_sliding_multiple.gif

http://tmedweb.tulane.edu/pharmwiki/lib/exe/fetch.php/regimens1a.png?w=600

http://besthealth.bmj.com/x/images/bh/en-gb/diabetes-injections_default.jpg

• Other agent that can improve glucose control are:– Pramlintide– Insulin pumps

http://www.emftesting.net/wp-content/uploads/2010/10/Insulin-Pump.jpg

http://blood-glucose-monitor.org/wp-content/uploads/2011/02/1298891488-58.jpg

http://t0.gstatic.com/images?q=tbn:ANd9GcRSizyl65SBOesFNMsSM1H9OtzwfCPa6WwLMfgzNHawNoTB8Ym3&t=1

TREATMENT OF TYPE II DMDRUGS MECHANISM OF ACTION

AGENT – SPECIFIC

ADVANTAGESAGENT – SPECIFIC DISADVANTAGES

BIGUANIDES (Metformin)

Reduce hepatic glucose production & insulin resistance, weight loss,

Weight loss Lactic acidosis, diarrhoea, vomitting

Alfa-Glucosidase inhibitors (Acarbose, Miglitol)

Reduce glucose absorption

Reduce postprandial hypoglycemia

GI flatulence, LFT elevated

Dipeptidyl Peptidase IV inhibitors (Sitgliptin)

Prolongs endogenous GLP-1 action

Do not cause hypoglycemia

Insulin secretagogues

Increase insulin secretion

Lower fasting blood glucose

Hypoglycemia, weight gain

Thiazolidinediones (Rosiglitazone, Pioglitazone)

Reduce insulin resistance, increase glucose utilisation

Lower insulin requirements

Peripheral edema, CHF, weight gain, fractures, macular edema

DRUGS MECHANISM OF ACTION

AGENT – SPECIFIC ADVANTAGES

AGENT – SPECIFIC DISADVANTAGES

INSULIN Increase glucose utilisation & other anabolic actions

Known safety profile

Weight gain, hypoglycemia

GLP-1 AGONIST (EXENATIDE)

Increase insulin, reduce glucagon, slow gastric emptying

Weight loss Increased risk of hypoglycemia with insulin secretogogues

AMYLIN AGONISTS (PRAMLINTIDE)

Slow gastric emptying, reduce glucagon

Reduce postprandial glycemia, weigh loss

Increased risk of hypoglycemia with insulin secretogogues

http://www.pharmainfo.net/files/images/stories/article_images/Major%20target%20organs%20and%20actions.jpg

TIKAL KANSARAINTERN

CIVIL HOSPITALAHMEDABAD