internal medicine training session (1); diabetes mellitus
TRANSCRIPT
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IInntteerrnnaall mmeeddiicciinnee ttrraaiinniinngg sseessssiioonn ((11)) DDrr.. AAhhmmeedd OOtthhmmaann
Case study (1)
Case Study
• 55 year old, obese man, routinely avoidmedical care presented to the clinic with a
fasting blood sugar of 108 mg/ml and a 2
hours post-prandial of 186 mg/ml.
DDi i aaggnnoossi i nngg DDi i aabbeet t eess Diagnosing Diabetes
Casual plasma glucose ≥ 200mg/dlAND symptoms
– Polyuria, polydipsia, unexplained weight
loss
Fasting plasma glucose of ≥ 126mg/dlAND symptoms
2 RBS or 2 FPG without symptoms
Oral Glucose Tolerance TestFasting
• Oral glucose load of 75g anhydrous glucose dissolved in water
• Plasma glucose testing at 2 hours
Oral Glucose Tolerance Test in pregnancyFasting more than 95
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• Oral glucose load of 100g glucose dissolved in water
• Plasma glucose testing at 3 hours
1 h more than 180
2 h more than 155 3 h more than140 When to screen…
•• SSccrreeeenniinngg f f oorr TT11DDMM iinnvvoollvveess tthhee mmeeaassuurreemmeenntt oof f aauuttooaannttiibbooddyy mmaarrkkeerrss ((aannttiibbooddiieess ttoo iisslleett cceellllss,,
iinnssuulliinn,, gglluuttaammiicc aacciidd ddeeccaarrbbooxxyyllaassee,, aanndd ttyyrroossiinnee
pphhoosspphhaattaassee))..
• Every 3 years for all individuals >45yo T2DM• More frequently or at a younger age if … BBMMII >>2255
-- HHyyppeerrtteennssiioonn
IInnaaccttiivvee -- HHDDLL225500
hh//oo gglluuccoossee iinnttoolleerraannccee -- PPCCOOSS
HHiigghh rriisskk eetthhnniicc ggrroouupp -- VVaassccuullaarr ddiisseeaassee
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hh//oo ggeessttaattiioonnaall DDMM --HHaavvee ddeelliivveerreedd aa bbaabbyy wweeiigghhiinngg 44kkgg
Targets for Treatment
HHbbAA11cc
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•• MMiiccrrooaallbbuummiinn mmeeaassuurreemmeenntt Nutritional Recommendation
• Provide individualized meal planningguidelines
• Carbohydrate training• Caloric balancing• Exercise
Oral Therapy
Typically reduces HbA1c by 2-3 pointsmaximum
CChhoooossiinngg aann OOrraall TThheerraappyy
•• GGlluuccoopphhaaggee ((MMeettf f oorrmmiinn)) – Increases sensitivity to endogenous insulin
– Decreases hepatic glucose production
– First line for obese patients
•• A Accaarrbboossee ((PPrreeccoossee)) – – DDeellaa y yss gglluuccoossee aabbssoorrppttiioonn
•• SSuullf f oonnyylluurreeaass – – IInnccrreeaasseess rreelleeaassee oof f eennddooggeennoouuss
iinnssuulliinn
– – FFiirrsstt lliinnee f f oorr nnoonn--oobbeessee ppaattiieennttss
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•• TThhiioozzoolliinnddiinneeddiioonneess – IInnccrreeaasseess iinnssuulliinn sseennssiittiivviittyy
Glucophage
AAddvvaannttaaggeess – – MMiinniimmaall wweeiigghhtt ggaaiinn
– – NNoo aaddddeedd rriisskk oof f hhyyppooggllyycceemmiiaa
AAddvveerrssee EEf f f f eeccttss – – GGII uuppsseett ccoommmmoonn
– – LLaaccttiicc aacciiddoossiiss ((uunnccoommmmoonn bbuutt 5500%% mmoorrttaalliittyy)) SSttaarrttiinngg DDoossee
– – 550000mmgg PPOO BBIIDD oorr 885500mmgg PPOO Q Q DD
– – IInnccrreeaassee bbyy 550000mmgg Q Q WWeeeekk
Glucophage
Contraindications
– – RReennaall iimmppaaiirrmmeenntt:: CCrreeaattiinniinnee >> 11..55 f f oorr mmeenn aanndd >> 11..44 f f oorr wwoommeenn;; ((ccaauuttiioonn iiss wwaarrrraanntteedd
iinn eellddeerrllyy ppaattiieennttss))
– – CCaarrddiiaacc oorr rreessppiirraattoorryy iinnssuuf f f f iicciieennccyy tthhaatt iiss
lliikkeellyy ttoo ccaauussee hhyyppooxxiiaa oorr rreedduucceedd ttiissssuuee
ppeerrf f uussiioonn
– – CCHHFF – – HHiissttoorryy oof f llaaccttiicc aacciiddoossiiss
– – SSuurrggeerryy
– – SSeevveerree iinnf f eeccttiioonn tthhaatt ccaann lleeaadd ttoo ddeeccrreeaasseedd
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ttiissssuuee ppeerrf f uussiioonn
– – AAllccoohhooll aabbuussee ssuuf f f f iicciieenntt ttoo ccaauussee aaccuuttee
hheeppaattiicc ttooxxiicciittyy
– – UUssee oof f IIVV rraaddiiooccoonnttrraasstt aaggeennttss
Glucophage
Others
CCiiddoopphhaaggee 550000-- RReettaarrdd 885500
GGlluuccoopphhaaggee 550000-- 11000000
SSuullf f oonnyylluurreeaass
Includes: – – gglliippiizziiddee ((GGlluuccoottrrooll// mmiinniiddiiaabb 55)),,
– – gglliimmeeppiirriiddee ((AAmmaarryyll //DDoollccyy)),,
– – ggllyybbuurriiddee ((DDiiaabbeettaa//MMiiccrroonnaassee)) -- GGlliibbeennccllaammiidd ((DDaaoonniill55 -- DDiiaabbeenn 55))uupp ttoo 33
-- gglliiccaazziidd(( DDiiaammiiccrroonn8800 --MMRR3300--6600)) aannttiippllaattlleess
Adverse Effects – – HHyyppooggllyycceemmiiaa
– –WWeeiigghhtt ggaaiinn
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TThhiioozzoolliinnddiinneeddiioonneess
Includes: – – rroossiigglliittaazzoonnee ((AAvvaannddiiaa))
– – ppiioogglliittaazzoonnee ((AAccttooss // aaccttoozzoonn 3300-- 4455)) 1155::4455
-- RReeppaagglliinniiddee ((DDiiaarrooll 00..55--11--22))
Contraindications – – CCllaassss IIIIII oorr IIVV CCHHFF
– – BBaasseelliinnee AALLTT >> 22..55xx nnoorrmmaall
Adverse Effects – – EEddeemmaa
– – WWeeiigghhtt GGaaiinn
Alpha Glucosidase inhbitorsWork on the brush border of the intestine
cause carbohydrate malabsorption
Advantages:
• Selective for postprandial hyperglycaemia• No hypoglycaemic symptoms
Disadvantages:
• Abdominal Distension and flatus• Only effective in mild hyperglycaemia
Alpha Glucosidase inhbitors
• Acarbose- 25 mg to 50mg thrice a day
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• Miglitol- 25mg to 100mg thrice a day
• Voglibose- 0.2 to 0.3 mg thrice a dayContraindications
• an inflammatory bowel disease, such asulcerative colitis or Crohn's disease; or any other
disease of the stomach or intestines
• ulcers of the colon• Intestinal Obstruction• kidney disease.
Sulphonylurea + Metformin
Includes: – – GGlliibbeennccllaammiidd++mmeett550000 ((gglluuccoovvaannccee))
– – GGllyybbuurriidd ((DDiiaavvaannccee 11..2255--22..55--55))
Incretin concept
• Insulin secretion dynamics is dependent on themethod of administration of glucose
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• Intravenous glucose gives a marked first andsecond phase response
• Oral glucose gives less marked first and secondphase insulin response, but a
prolonged and higher
insulin
concentration
Insulin secretion profilesIso-glycaemic profiles
What are the incretins?
• GIP: Glucose-dependent insulinotrophic polypeptideSmall effect in Type 2 diabetes.
• GLP-1(glucagon-like peptide 1)augmented in the presence of hyperglycaemia.
Action less at euglycaemia and in normal subjects.
• Pituitary Adenylate Cyclase Activating Peptide(PACAP)
GLP-1 Modes of Action in Humans
Now for the bad News…………..
GLP-1 is short-acting
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Dipeptyl- peptidase inhibitors
Sitagliptin
VildagliptinSaxagliptin
Septagliptin
Allogliptin
DPP-4 Inhibitors
•• SSiittaagglliippttiinn ((JJaannuuvviiaa)) •• SSaaxxaagglliippttiinn ((OOnnggllyyzzaa)) •• LLiinnaagglliippttiinn (( TTrraadd j jeennttaa)) TTaakkee oonnccee aa ddaayy aatt tthhee ssaammee ttiimmee eeaacchh ddaayy IImmpprroovveess iinnssuulliinn lleevveell aaf f tteerr aa mmeeaall aanndd lloowweerrss tthhee
aammoouunntt oof f gglluuccoossee mmaaddee bbyy yyoouurr bbooddyy
Side effect
SSttoommaacchh ddiissccoommf f oorrtt,, ddiiaarrrrhheeaa,, ssoorree tthhrrooaatt,, ssttuuf f f f yy nnoossee,, uuppppeerr rreessppiirraattoorryy iinnf f eeccttiioonn..
Comparing the GliptinsSitagliptin Vildagliptin Saxagliptin
Dosing OD BD OD
Renal Failure Approved Not Approved Approved
Hepatic Failure No info No info
Safe
With Insulin Not Approved Approved
Studies Pending
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On Bone Improved BMD? Unknown
Unknown
Infections Slight increase NeutralNeutral
UTI, URI
Cardiac Impact RReedduucceedd Neutral
?reduced CV mortality
post ischaemic stunning
Which is the appropriate oral hypoglycaemic agentto use and when?
Mechanism of Action of Sitagliptin
Determinants of OAD usage1)Body Mass Index : Metformin, Gliptins
BMI> 22kg/m2
2)Presence of GI symptoms: Sulpha, Gliptins, Glitazones
3)Renal Dysfunction: Gliptins,Glitazones(+/-),Sulpha (variable)
4) Aging Meglitinides,
Gliptins(?)
5) Hepatic Dysfunction Nateglinide, Saxagliptin(?)
6) Compliance Gliptins, Glitazones,
7) Cost Metformin,
Sulphas, Glitazones
Back to our patient
• During the next five years he was not compliant to his
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medications despite
• having laser treatment for his left eye twice. And in thelast few months
• he noticed edema of his lower limbs.
IInntteerrnnaall mmeeddiicciinnee ttrraaiinniinngg sseessssiioonn ((22)) DDrr.. AAhhmmeedd OOtthhmmaann
Case study (2)
• A 32-year-old male with type 1 diabetes since the ageof 14 years was taken to the emergency room because ofdrowsiness, fever, cough, diffuse abdominal pain, and
vomiting.
• Fever and cough started 2 days ago and the patient couldnot eat or drink water.
• He has been treated with an intensive insulin regimen(insulin glargine 24 IU at bedtime and a rapid-acting insulin
analog before each meal )
Case study (2)
• On examination he was tachypneic.• His temperature was 39° C.• pulse rate 104 beats per minute,• respiratory rate 24 breaths per minute,• supine blood pressure 100/70 mmHg;
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• he also had dry mucous membranes, poor skin turgor, andrales in the right lower chest. He was slightly confused
Case study (2)
• Investigations:• hemoglobin 14.3 g/dl ,• white blood cell count 18,000/ μ l,• glucose 450 mg/dl,•
creatinine 1.2 mg/dl ,
DKA Definition
Pathophysiology
Etiology
• Insulin deficiency Insulin missed dose Pancreatitis Heavy meal
• Excess Counterregulatory hormones
• Infection i.e. Pneumonia• MI• Stroke• Trauma• Emotional
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• Pregnancy• Iatrogenic
Clinical manifestations
• Special notes• Abdominal pain It is more common in children than in adults It is multifactorial
dehydration of muscle tissue
Delayed gastric emptying Ileus from electrolyte disturbances Metabolic acidosis;
It sometimes mimicks acute abdomen It is classically periumbilical
Differential Diagnosis
• DD of acidotic breathing – Renal failure – Amonia increase in HCF – Hysterical
• DD of diabetic coma
– Lactic acidosis – Hyperosmolar non-ketotic coma – Hypoglycemia
• DD of coma in general
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• DD of acute abdomen
DKA vs. HHS
DKA vs. HYPOGLYCEMIAInvestigations
For diagnosis
Triad for diagnosis
• RBS Hyperglycemia > 250 mg/dl• Ketonemia and ketonuria
• Blood gas metabolic acidosis – pH < 7.35, anion gap (Na + K) – (Cl + Bicarb) > 10, and Bicarbonate
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For Monitoring
•• RRBBSS –
Every 1 hour till RBS reaches 200 mg/dL or less, then
every 6 hours
•• UUrriinnee kkeettoonneess – Every 8h
• BBlloooodd ggaass after fluid replacement• EElleeccttrroollyyttee sseerruumm lleevveell every 4 hours till correctionTreatment of DKA
• Treatment of predisposing factors• Initial hospital management
– Care of comatosed patients – Fluid and electrolytes replacement – Insulin replacement and glucose administration when
needed
– Treatment of complications
• Once resolved – Convert to home insulin regimen
– Prevent recurrenceFluids and Electrolytes
• Fluid replacement – Restores perfusion of the tissues
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– Average fluid deficit 3-6 liters• Initial resuscitation with saline
– 1 L of normal saline over the first ½ hour then – 1 L of normal saline over ½ hour then – ½ L of normal saline over 1 hour then – ½ L of normal saline over 2 hours
– Then the rate will depend on clinical judge(BP, CVP, basal lung crepitation)
Fluids and Electrolytes
•• KK++ lleevveell ((cchheecckk aatt 00,,22,,66,,1100,,2244 hhr r )).. – If Hyperkalemia (> 5.5 meqlL)
• initially present•
No treatment as it resolves quickly with insulin drip – If normal level (3.5-5.5 meqlL)
• Add 20-30 meql for each Liter of infused fluid
– If Hypokalemia (
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• If corrected Na is Low use NS, rate depends on severity ofvolume depletion
Insulin Therapy
• Initial dose – IV bolus of 0.1-0.2 units/kg (~ 10 units) regular insulin – Infusion insulin at 0.1 units/kg/hr (max 8 units/hr).
• Maintenance dose (Check BG Q1hour, goal is 50-80 mg/dl/hr ) –
If falling too rapidly, decrease the rate – If falling too slowly increase the rate by 50-100%
• Continue IV insulin until urine is free ofketones and RBS reaches 250-300 mg/dl
Insulin Therapy
•• WWhheenn RRBBSS rreeaacchheess 225500--330000 mmgg//ddll –
Decrease the rate of insulin infusion to 0.05-0.1 IU/kg/hr(goal is to keep RBS in this range until the gap closes(normal gap 7-8 mEq/l)
– then start home maintenance SC insulin underumbrella of infused insulin for 2 hours, then
continue on SC insulin only .
Glucose Administration
• Supplemental glucose – Hypoglycemia occurs
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• Insulin has restored glucose uptake• Suppressed glucagon
–
Prevents rapid decline in plasma osmolality
• Rapid decrease in insulin could lead to cerebral edema
• Glucose decreases before ketone levels decrease• Start glucose when plasma glucose < 300
mg/dl
Insulin-Glucose Infusion for DKA
Complications of DKA
Causes of Cerebral EdemaMechanism:
• The brain adapts by producing intracellular osmoles (idiogenic osmoles) whichstabilize the brain cells from shrinking while the DKA was developing.
• When the hyperosmolarity is rapidly corrected, the extracellular fluids is correctedfaster than brain cells
– The brain becomes more hypertonic than the extracellular fluids water flows into the cells cerebral edema
Causes of Cerebral EdemaThe many factors have been implicated:
Rapid and/or sharp decline in serum osmolality with treatment. High initial corrected serum Na concentration. High initial serum glucose concentration.
Failure of serum Na to raise as serum glucose falls during treatment.
Presentations of Cerebral Edema
CCeerreebbrraall EEddeemmaa PPrreesseennttaattiioonnss iinncclluuddee::
Deterioration of level of consciousness.
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Headache and blurring of vision Vomiting
Convulsion.Treatment of Cerebral Edema
• Reduce IV fluids• Raise foot of Bed• IV Mannitol• Elective Ventilation• Dialysis if associated with fluid overload or renal failure.• Use of IV dexamethasone is not recommended.
Prevention of DKA
• Never omit insulin – Cut long acting in half
• Prevent dehydration and hypoglycemia• Monitor blood sugars frequently• Monitor for ketosis• Provide supplemental fast acting insulin• Treat underlying triggers• Maintain contact with medical team
Pitfalls in DKA
• Plasma glucose is usually high but not always
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– DKA can be present with RBS < 300 due to• Impaired gluconeogenesis
– Liver disease – Acute alcohol ingestion – Prolonged fasting – Insulin-independent glucose is high (pregnancy)
• Chronic poor control but taking insulin
• Ketone in urine may be –ve in DKA, but always +ve in blood – Due to measurement of acetoacetic acid in urine not,
betahydroxybuteric acid
– Acetone in blood should be done in this case
Pitfalls in DKA
• High WBC may be present without infection• Infection may be present without fever• High Creatinine may be present without true renal function: it
may cross react with ketone bodies.
• Blood urea may be elevated with prerenal azotemiasecondary to dehydration.
• Serum amylase is often raised even in theabsence of pancreatitis
Case study (3) A 82-year-old male patient was taken to the emergencyroom in the afternoon for loss of consciousness in theprevious hour.
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The patient had hypertension, chronic ischemic heartdisease, and mild diabetes treated with glibenclamide daily.
On examination the patient had coma (Glasgow scale 5)
and right hemiplegia.
Whipples triad
• Symptoms consistent with hypoglycemia• Low plasma glucose concentration
• Relief of those symptoms after the plasma glucoselevel is raised
Risk factors
insulin doses are excessive, ill-timed, or of the wrongtype
influx of exogenous glucose insulin-independent glucose utilization sensitivity to insulin endogenous glucose production insulin clearance
Clinical features
MMIILLDD HHYYPPOOGGLLYYCCEEMMIIAA
- mainly adrenergic or cholinergic symptoms
Pallor
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Diaphoresis Tachycardia
Palpitations Hunger Paresthesias
Clinical features
MMOODDEERRAATTEE HHYYPPOOGGLLYYCCEEMMIIAA ((
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Oral carbohydrates (at least 15gm) Sources include
•
Three glucose tablets (5g each)
• 2 ½ cups of fruit juice• ½ to ¾ cup regular soda• 1 cup of milk
If patient is unable to take orally give IV dextrose
Treatment
MMOODDEERRAATTEE TTOO SSEEVVEERREE HHYYPPOOGGLLYYCCEEMMIIAA
Dextrose - 50mL of 50% dextrose IV bolus followed by 10%dextrose
Glucagon – 1mg IM or SC can be given Effective in treating hypoglycemia only if sufficient liver
glycogen present
These measures raise blood glucose only transiently Patient is urged to eat as soon as possiblePrevention
Patient education Knowing signs and symptoms of hypoglycemia Take meals on a regular schedule Carry a source of carbohydrate Self monitoring of blood glucose Take regular insulin at least 30 min before eating
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QUESTIONS