Endocrine Mbchb4

DIABETES - TREATMENT

Glycaemic Targets
• HbA1c 6.5-7.5% (glycated Hb normal 4-6% but unreasonable targets guarantees failure) – ave blood sugar level = HbA1c x 2 – 5 (approx)

Dietary Therapy (for all)
• ↓ refined carbs
• ↓ fat
• Hypocaloric (if overweight which incl most T2DM pts)

Weight Loss
• ~65% of diabetes in men and women would be prevented if there were no BMIs >25 kg/m2
• Sugical tx – 87% diabetes reverted to normal blood glucose after gastric bypass procedures
• Drug tx
• Sibutramine (Reductil) – SSRI type drug, ↑ metab rate, feel full faster; 5% weight loss + plasma glucose ↓ by 1.4 mmol/L
• Xenical (Orlestat) – inhibits fat absorption in SB (lipase inhibition); s.eff incl steatorrhea, diarrhea, flatus (common)

Drug Tx T2DM – Hypoglycaemic Agents

Indications – inadequate glycaemic control despite diet
A. Biguanides (Metformin) or Sulphonylureas
1. Metformin
• ↑ tis sensitivity to insulin (unclear mechanism) - ↓ insulin resistance
• Does not cause hypoglycaemia
• Tends to promote weight loss (other drugs usu promote weight gain)
• S.eff – nausea, abdo pain, diarrhea
• Dose 1-3g daily w food (500 or 850 mg tablets)
• Contraindications - due to lactic acidosis; rare but fatel (a. CRF creat >160 umol/l, b. chr liver dis ie cirrhosis, c. severe HF)
2. Sulphonylureas
• ↑ insulin secretion from B cell
• Can cause hypoglycaemia
• Tend to encourage weight gain
• Dose range (glipizide) of 2.5-20 mg daily
• Dose response flat at upper end
• Sulphonylurea induced hypoglycaemia – occurs in elderly (esp if malnourished + renal impairment), worse w long acting drugs, may be long lasting
• NZ Availability
• Tolbutamide 500mg Short acting
• Gliclazide 80mg Max dose 2 tablets bd (most prescribed in nz; 40-320mg daily)
• Glipizide 5mg 2.5-20mg daily
• Glibenclamide 5mg Long acting (avoid in elderly or renal impairment); 2.5-20mg daily
B. Other Drugs
• Acarbose
• Delays glucose absorption by inhibiting conversion complex CHO to simple CHO
• Reduces post prandial glucose
• S.eff – prominent due to fermentation of CHO in gut (many patients avoid acarbose for this reason)
• Thiazolidinediones
• Rosiglitasone (Avandia; 4-8mg) or Pioglitazone (Actos; 30-45mg; 1st line tx USA)
• PPAR agonist – improve insulin sensitivity
• Redistribute fat from central to peripheral regions
• Improve lipid profile, ↓ FFA
• Low risk hypoglycaemia
• S.eff – weight gain, edema (contra HF as exacerbates HF), recent concerns re loss of bone density and fractures, concerns re ↑ CVS mortality (2x)
• GLP1 Agonists
• Insulin incretins – food in SB causes release of GLP1 (glucagons like peptide) → stimulates insulin release and inhibits glucagons + slows gastric emptying
• GLP1 is deficient in pts w T2DM
• Exenatide – injectable LA agonist, ↓ glucagon, ↑ insulin, slows gastric emptying (s.eff nausea)
• Sitagliptin (Januvia; 100mg od) – oral once daily inhibitor of enzyme that breaks down GLP1 (DPP4), therefore ↑ GLP1 → ↑ insulin, ↓ glucagon; effective and no major s.effects but v new agent so LT outcome unknown; added benefit of weight loss due to feeling of gastric fullness
• Janumet = Metformin + Sitagliptin


Insulin Therapy in T2DM Patients

• Indications
• Sxs of insulin deficiency – weight loss, lassitude, ketosis, failure of oral hypoglycaemics, diet or natural hx, pregnancy in T2DM (and GDM), surgery or intercurrent illness in T2DM (incl glucocorticoids), newly diagnosed T2DM requiring temporary use of insulin
• **50% of T2 pts need insulin within 10y
Insulin Types Insulin Peak Novo Nordisk Ely Lilly
Ultra SA 1-2 h Aspart (Novorapid) Humalog
SA 2-4 h Actrapid Humulin R
IA (tx mainstay) 4-16 h Protophane Humulin N
Mixtures Syringe Mixtard 30/70 Humulin 30/70
Mixtures Pen device Penmix 30/70 Humulin 30/70
Inuslin Glargine (Lantus) is LA (24h) insulin analog said to provide a basal insulin profile w/o a peak (only available in NZ for T1DM pts)

Outpatient Insulin Regimes
• Nocturnal IA + daytime oral hypoglycaemics
• 1x daily - LA (day or night) – T2DM
• 2x daily – usu mixed short or intermediate acting – T2DM
• 3x daily – Mixed before breakfast, SA at evening meal, IA at bed – T2DM
• 4x daily – SA pre-meals, IA at bed – T1DM / T2DM
• Continuous subcut insulin (variable basal rate plus variable meal bolus using ultra SA or SA) – T1DM

Adjusting Insulin
• Look for reproducible patterns and adjust appropriate insulin
• Changes should be ~10-15% and not made more than every 3 days
• Chaotic patterns difficult to manage; contributory problems include
• Poor injection technique
• Hypoglycaemia avoidance
• No monitoring
• Eating pattern
• Fat hypertrophy at injection sites
• Too freq dose adjustment
• Missing injections

Hypoglycaemia
• Mild – detected and corrected by pt
• Severe – involves another person
• Risk of hypogly – inversely relates to degree of glycaemic control (ie ↓HbA1c ↑ the risk of hypoglycaemia; the major factor limiting aggressive control; a pt becomes accustomed to low bld sugar levels, no adrenalin kick occurs and pt goes straight into coma)
• Hypgly awareness may be lost after several years w T1DM and can be improved by meticulous avoidance of hypogly
Causes of severe hypogly
• Insulin error
• Unusual exercise
• Alcohol
• Missed meals
• Adrenal or pituitary insufficiency
• Weight loss
• Honeymoon period
• Tx – glucose by mouth, IV glucose, glucagons injection

Inpatient Insulin Regimes
• Not seriously ill + glycaemic control good → continue usual regimen
• Elective surgery + glycaemic control good → GIK regimen (glucose-insulin-potassium)
• Unstable diabetes → variable rate insulin infusion; not sliding scales

Home Blood Glucose Measurement
• Regular monitoring (freq according to meals and usefulness)
• Trouble shooting
• Guide to insulin dosage

DIABETES - COMPLICATIONS

Microvascular – 1. Retinopathy, 2. Nephropathy, 3. Neuropathy
Macrovascular – 1. Cerebrovascular dis, 2. IHD, 3. PVD

MICROVASCULAR COMPLICATIONS
T2DM patients may already have these complications at dx of DM because they can remain undx for long periods
Main determinants for the development of microvascular complications are duration of DM and glycemic control

1. Retinopathy
5+ yrs to develop
a. Early stages micro-aneurysms (dots), small circ hemorrhages (blots) +/- exudates classified as background retinopathy of varying severity (not sight thr)
b. Deteriorating stage pre-proliferative retinopathy characterised by flame-shaped hemorrhages, venous tortuosity + cotton wool spots
c. Advanced stages devt of new retinal vessels, proliferative retinopathy, sight threatening, vitreous hemorrhage can cause retinal detachment w perm sight loss
Detection Axs until v advanced → diabetic pts should be screened for eye dis at regular intervals (2 yearly)
Pts w known eye dis should be under ophthalmogical supervision
Tx Good glycemic control prevents devt and progression
Laser therapy for pre-proliferative and proliferative retinopathy prevents blindness (Complications - loss of peripheral and night vision)
Other procedures – eg vitrectomy
BP reduction and smoking cessation

2. Neuropathy
Nat hx Periph neuropathy most common manifestation (Predominantly sensory affecting feet and legs)
Early stages – asx or symptomatic (dysaesthesia, paraesthesia)
Late stages – anesthetic feet prone to ulceration and or pressure areas
Advanced stages – neuropathic (charcot) joints, recurrent ulceration, neuropathy of hands
Autonomic neuropathy
Most common – erectile dysfunction
Advanced dis – gastroparesis, diarrhea, neurogenic bladder, postural hypotension
Detection Sensation testing – vibration, pressure and lost ankle reflexes
Tx Good glycaemic control
Education and podiatry services for pts w at risk feet
Tx of co-existing PVD
Ulceration – non-weight bearing, antibiotics, surgery to remove necrotic/infected tis, glycaemic control

3. Diabetic Nephropathy
Path - Basement membr thickening + mesengial expansion → glomeruli become sclerosed and obliterated (later stages)
Nat hx
10-20 yrs
Defining clinical and lab findings – 1. BP, 2. Albuminuria, 3. Renal function (eGFR)

Stage → Normal Incipient Established Advanced
1. BP Normal for age Raised + Raised ++ Raised +++
2. Albuminuria (mg/day) or Albumin/Creatinine ratio (mg/mmol) <30
<3 30-300 (microalbuminuria)
3-30 300-3000 (macroalbuminuria)
30-300 >3000 (nephrotic range)

3. GFR (ml/min) Normal or ↑ for age Normal or ↑ for age Declining (≈1ml/min/month) <15 (end stage uraemia)
Once stage of ↓ GFR reached → progression to end stage renal failure is inevitable w/o tx
Vicious cycle where HT causes further glomerular damage which in turn worsens the HT
Control of HT will arrest/slow progression of nephropathy

Prenventn Maintainence of good glycemic control (measure via HbA1c)
Tx 1. ACEI/ARB → ↓ albuminuria and preserve renal function over and above their hypertensive effects (1st line tx for diabetic nephropathy)
2. Other anti-hypertensives

HT in T2DM
Extremely common as most have the metabolic syndrome (glucose intol + HT + dyslipidemia + endothelial cell dysfunction + abdominal obesity)
All these factors (+ smoking) → sig RFs for CV dis → main cause of premature morbidity in this popn
↓ HT → ↓ CV risk
End-stage chronic RF assoc w –
High rates of CV dis – stroke, TIA, angina, MI, HF, claudication, gangrene
Advanced microvascular complications – visual loss, blindness, foot ulceration, bladder, gastric problems

Hypertensive Nephropathy
Chr HT = leading cause of Chr RF and presents similarly to diabetic nephropathy w HT, progressively worsening albuminuria, ↓ RF and inactive urine sediment (ie no casts or red cells in MSU)
Can be difficult to say whether diabetic or hypertensive nephropathy is the dominant cause, but est nephropathy (in absence of diabetic retinopathy) suggestive of HT
Principles of mgt of both diabetic and hypertensive nephropathy are the same

Hypertension Tx
Aggr tx ↓renal func decline AND ↓ CV risk
Target BP 130/80
Sequential anti-hypertensive drug use
1. ACEI or ARB (first line) – ?combined ACEI/ARB
2. + diuretic (thiazide or frusemide)
3. + CCB (felodipine)
4. + b-blocker
5. + a-blocker
Problems Inadequate dosage – aim to get ACEI/ARB to maximum
Failure to reach target BP – 2+ agents may be reqd
Hyperkalemia concerns – ACEI/ARB both K-sparing and ↑ K w ↓ GFR → ↑ plasma K (counteract with K-losing diuretics – frusemide, thiazides)
Avoid K sparing diuretics – spironolactone, amiloride
Renal function concerns – ACEI/ARB → sig ↓ in GFR when first started (due to impaired renal autoregulation) – continue anyway
Renovascular dis concerns – a large ↓ in GFR above → consider renal artery stenosis (only assess pts w >33% ↓ from baseline GFR for renal art dis)

Non-progressive microalbuminuria
Microalbuminuria does not specifically indicate diabetic +/- hypertensive nephropathy
Low level non-progressive or intermittent microalbuminuria can be seen with –
Episodes of poor glycemic control
After unusual exercise
Post-partum
Manifestation of endothelial dysfunction

Other common complications of diabetes
a. Mononeuropathies – usu recover (incl femoral neuropathy), CN3 and 6 palsies
b. Cataracts
c. Cutaneous/Subcutaneous – ↑ infections (cellulites, UTI, candida), carpal tunnel, trigger finger,

MACROVASCULAR COMPLICATIONS

a. Epidemiology of CVD and DM
Absolute risk – 2-4x ↑ (T1 and 2)

CVD responsible for 75% of diabetic hosp admissions or deaths
Risk esp high when overt nephropathy (>300 mg/albumin/24 hr)
Lipids,smoking, HT do not a/c for excess risk in these pts

b. Clinical presentation
1. IHD – 2-4x ↑ prevalence, diabetic pts poorer prognosis following MI, more extensive and more distal coronary art dis
2. HF – due to ↑ incid of HT and IHD (more silent MIs)
3. Stroke – 2x↑ prev, survival worse
4. PVD – 4x↑ prev, propensity for distal atherosclerosis, prox dis also ↑

c. Causal Factors – Hyperglycemia, BP, Lipids

d. Risk Factor Modification
1. Glycaemic control (HbA1c <7%) - reduction appears to be more effective for microvascular dis
2. BP control (<130/80) – for any given BP, CV risk 3x ↑ in diabetic pts – first line ACEI then others
3. LDL <2.5 (or even <1.6), TG <1.7, HDL >1 – for any given total chol, CV risk 4x ↑ in diabetics → statin therapy regardless of baseline chol
4. Aspirin
5. Smoking cessation

Key Points
DM pts 2-4x ↑ CV risk
Most will die of CVD
Hyperglycemia is related to macrovascular dis risk in T1 and T2
Nephropathy substantially ↑ CV risk
DM worsens prog in AMI, HF and Stroke
BP and lipids should be aggr tx
Multiple CV RF intervention effective

IDDM
• Destruction of islet B cells w conseq absol insulin deficiency and dependence on insulin tx for survival
• Peaks of incidence in Caucasians aged 5 and early adolescence but new cases can occur at any time – a percentage of slower developing cases are now recog in adults – about 10% of all cases DM in NZ
• Failure to replace insulin leads to diabetic ketoacidosis (almost always fatal w/o therapy)
• Presumed auto-immune basis w round cell (lymphocyte, macrophage) infiltrates of the islets, anti-islet and primary anti-insulin antibodies – not universally accepted theory
• Familial – about 50% concordance rate betw identical twins reared apart
• Interaction betw poorly defined etal factors (eg viruses) and a genetic predisposition
• Molecular basis now beginning to be understood – demonstrated assoc in some popns w specific residues at the 57th pos of MHC DQ8 molec – several candidate genes both in the MHC and elsewhere identified
Insulin therapy
• Insulin is a protein so must be administered parenteral route to avoid digestion which would inactivate it
• Normal route subcutaneous injections
• On occasions (eg during surgery, ketoacidotic coma, mgt of labour in mother w diabetes, certain syndromes of insulin resistance etc), insulin given by IV infusion to ensure secure delivery of precisely known amounts
• Standard replacement dose in adult w no complications is about 21-24 Units/day of which some 2/3 given usu before breakfast and the rest later in the day
• Use of self-blood glucose monitoring to assess control on a daily basis and a measurement of glycosylated protein (eg glycosylated hemoglobin) to monitor degree of control over a longer period (weeks to a few months)
• Major limiting feat is hypoglycemia – which will occur regularly in most pts on insulin therapy for IDDM
Diabetic Ketoacidosis
• End result of a lack of insulin
• Can occur either as first presentation IDDM or in a pt whom insulin is not working (eg intercurrent infection has induced progressive insulin resistance w/o compensation)
• Starvation in the midst of plenty – the body is unable to use glucose owing to the lack of insulin – so instead is forced to break down and oxidize TG
• As a byproduct – formation of ketone bodies (acetone w characteristic odour detected by 80%, acetoacetate and B-hydroxybutyrate – 5:15:80) – former two can be detected by reaction w nitroprusside (urine dipstick purple)
Mechanism
• Osmotic Diuresis
o Lack of insulin leads to hyperglycemia and resulting osmotic diuresis, w accompanying loss of water and elytes (Na, K, Mg, phosphate) in urine
• Ketone body generation
o Inability to use glucose due to absol lack insulin means body has to switch to using TGs as fuel (ie starvation response)
o This generates large amounts of B-hydroxybutyrate and acetoacetone (acids) which cannot be cleared efficiently due to their rate of prodn and which therefore accumulate in the blood and add to osmotic diuresis
o Can get accum or large amounts lipoprotein in blood w resultant excluded vol effects
• Metabolic acidosis w initial respiratory compensation
o Accum of organic acids produces a metabolic acidosis (w progressive elevation of anion gap)
o This elicits respiratory compensation (hence acidosis w low bicarbonate and low pCO2, characteristic tachypnoea (kussmaul breathing)
o H+ ion in the ECF is initially buffered by extracellular buffer syss (bicarbonate, protein) and also intraceullar buffering (exchange w intracellular K and Mg) which leads to ↑ loss of these ions in urine
• Progressive dehydration
o Fall in blood vol and conseq onset of pre-renal failure – as the course of metabolic dysfunction progresses, effectiveness of the respiratory compensation lessens and at the same time, pts become progressively exhausted – this can lead to progressive failure of respiratory compensation and late in the process, to a 2ndry respiratory acidosis – at this time, reduction in consciousness can ensue and death follows unless the process is reversed
• Tx of dKa
o IV fluid and elyte replacement w IV insulin and careful use of bicarbonate in the event of severe acidosis
o Response usu good but dka is still v dangerous condition
o There is a need for freq monitoring elyte levels
o Although blood levels of intracellular ions (K, Mg, PO4) are often elevated on presentation, this can mask severe body deficits
o When therapy begins to take effect, pH falls and renal output picks up – there can be rapid shifts of in partic K back into intracellular c/ment – this can lead to lifethreatening hypokalemia (arrhythmia) unless K is monitored and replaced
o A second metab complication of the therapy of dka is the usual presence of insulin resistance, which may be quite severe
o Thus it is necessary to ↓ IV insulin doses carefully, looking for recurrence of hyperglycemia and ketosis
• LT Mgt
o Diet
o Exercise
o Insulin and self blood glucose monitoring
o Education – specialist diabetes nurse educator, support groups
o Lifestyle monitoring
o Regular follow-ups and screening for complications
o Special issues – childhood, adolescence, pregnancy

NIDDM
• Usu occurs later in life w progressive ↑ prevalence through the 7th decade
• Strong familial tendency – near total concordance rate betw identical twins reared apart, however recent evidence suggests that effects of intrauterine evt must be examined critically
• Rapid rise in prevalence in 3rd world popns undergoing transition to a first world economy – high prevalence among maori, pacific islanders in NZ
• Epidem evidence suggests most NIDDM pts have passed through an initial period of IGT but note that only one in four who develops IGT go on to develop NIDDM
• Clustering w obesity, essential HT, atherosclerosis
• Once established, rate of devt of chr diabetic complications occurs at a rate similar to that in IDDM
• Dis shows progression from initial IGT through a stage of ↑ insulin output and insulin resistance to an endstage of progressive failure insulin secretion (2ndry failure) w ↑ requirement for insulin therapy
Disease Mechanims
• Biol mechanisms remain obscure
• Characterized by 3 path findings –
o insulin resistance – skeletal mus and liver – structurally abnormal insulins, insulin receptors
 GLUTs in peripheral tissues now excluded as mechanisms of NIDDM
o abnormal insulin secretion – progressive loss of first phase insulin secretion, selective glucose blindness of islets
 possible role of defective glucokinase in MODY
o islet amyloid – present in large majority, abnormal protein deposits in islets adjacent to B cells, contain islet B cell peptide amylin, likely role in disruption of islet architecture and late deterioration of insulin secr
IGT
• dx by oGTT
• suspect via risk factors
• equivalent risk of large vessel dis as NIDDM – but NO diabetes specific compliations
Tx
• mainstay early tx – diet
o ↓ calorie intake (fat, meat, refined sugars)
o ↑ intake complex (non-processed carbs)
• ↑ exercise if it can be tolerated but beware foot probs
• w established hyperglycemia in the presence of diet, go to oral hypoglycemic agents – sulphonylureas, consider metformin if obese) w monitoring of therapy by SBGM and glycated protein measurements in addition to screening for complications
• diabetes education
• w failure of sulphonylurea therapy – diet and max doses of relevant compounds (2ndry failure) – consider switching to insulin therapy
• need for vigilance for complications – incl foot dis leading to gangrene
Complications of NIDDM
• chr vascular complications occur in NIDDM w equivalent freq to IDDM
• non-ketotic hyperosmolar coma – similar in ways to DKA but no acidosis – due to residual insulin prodn allowing mtab of ketone bodies – a severe complication which requires intensive hospital mgt
• lactic acidosis – rare complication of metformin therapy – usu in assoc w underlying alcoholism, liver dis or renal dis (all of which are absol contras for metformin use)

Hypoglycemia
• occurs when blood glucose levels fall too low to maintain brain function
• usu deteriorates progressively when glucose falls below 2.5mmol/l
• diff pts have diff thresholds for sx
• w chr starvation – or w heavy prolonged exercise, can see glucose levels down to 1.0 mmol/l w/o hypoglycemia sx – however in these situations, have ↑ FFA mobilization and ketone body prodn w switch to these sources for some energy requirements (brain can slowly switch to use ketone bodies for up to half of its total energy requirement, but nevertheless remains absolutely dependent on glucose for the other half – this is an adaptation which usu takes at least sev hours to days)
• sx fall into two grps –
o adrengergic – usu predominate, pallor, sweating, tremor, palpitations, dry mouth
o neuroglycopaenic – brain short of glucose, lack of concentration, slow mvments, slurred speech, double vis, personality changes, transient stroke, fits, coma (not infreq can be mistaken for alcohol intox)
o sequelae – usu no obvious, permenant effects – prognosis for recovery declines w length of coma, outcome worse if assoc w hypoxaemia or hypotension
Classification
• Fasting Hypoglycemia
 Provoked by starvation or stimes by exercise
 Always indicates an identifiable underlying cause
o Excess Insuln-like activity
 Insulin overdose – occurs repeatedly in most pts undertaking intensive insulin therapy to achieve normoglycemia
 Insulinomas
 Factitious hypoglycemia – surreptitious intentional overdose
 Other substances which stimulate the insulin recepotor
 Sulphonulurea overdose
o Hepatic dysfunction
 Severe infections
 Ethanol toxicity
 Malaria
 Severe parenchymal liver dis
 Drugs eg salicylate poisoning
 Deficiency of hormones – eg cortisol/ACTH, GH
• Reactive Hypoglycemia
o Related to operations which have produced excessive rate of gastric emptying w consequently elevated stimulation of insulin secr and insulin-induced hypoglycemia
o Occasionally early in devt of NIDDM – discordinated excessive insulin secretion 3-5 hrs post meal (dx w prolonged oGTT)
o Occasionally in otherwise normal pt - controversial
Tx
o Glucose/sugar etc – by mouth if tolerated or IV if not
o If glucose not avail - glucagons IV or IM – this must be followed by glucose or food as it wears off in about 30 mins – glucagon not effective in situations w abnormal liver function/depleted glycogen stores

Supplementary – Lecture Notes

o Sulphylureas – augment insulin secretion – only work for small period of time → progressive failure to wor
o ¾ diabetic pts will die from CV complications – microvascular and macrovascular
o ¼ diabetic pts will die from kidney dis
o ½ DM – undx in NZ – so will present as diabetic complications
o 2 routes to identification of DM – symptomatology + risk factors
o post-prandial aka random
o hyperglycemia does not occur in isolation – occurs w hyperlipidemia and HT
o protein glycation – adding glucose to protein
o HbA1C – total % <6% in normal person (all people have some) but will ↑ (>8%) in IGT/DM
o Macrosomia complications – both fetal and maternal trauma at delivery and babies will often become hypoglycemia due to ↑ B-cell mass in pancreas (after birth → excessive insulin prodn) → irreversible brain damage – prevention is by dealing w maternal diabetes during preg
o GDM – gone within 6 wks post partum - intensifies w each preg
o Honeymoon phase – in IDDM, insulin not reqd after initial tx (B-cells initially partially recover but then regress over 3-12 months) – will require insulin w time
o Tx triad – nutrition, lifestyle/exercise, medication
o 2 forms of insulin – short and long acting – to last the whole day
o SBGM – finger prick on the side of the finger not the tip (less nerves)
o Eye screening – proliferation of vessels outgrowing blood supply and eventually hemorrhaging
o 1 episode of DKA – considered type 1 diabetic for life

303 - LECTURE – DIABETES CLINICAL

Case 1 - HONK

1. Initial Presentation - 65 M - presenting w cellulites R lower leg – infection settled quickly w a/bs - GP request GTT – fasting glucose 7.3 mmol/l and 2 hr bld glucose 8.0 mmol/L
Was it reasonable to request a GTT – what does it show?
• Infections are a common presentation of diabetes
What else would you like to know from hx and examination?
• Family hx (father had type 11 DM), nutritional status (weight 90kg, BMI 29) and changes in weight (had gained weight over previous 3 yrs, no recent weight loss – BP 146/94 – smokes a pipe
Would any additional tests be helpful?
• Lipids (T/HDL 4.7 and TG 2.1)
How should the condition be managed?
• Diet initially - ↓ fat, more exercise, weight loss

2. Two years Later – Fishing trip – began to feel dry and thirsty - Freq stops to urinate on way home - Felt weak and exhausted and spent day in bed – in the morning, blood sugar test showed 68mmol/L – admitted to hospital
What is the likely dx?
• HONK – hyperglycemic coma
What additional hx would be useful?
• Other sx of DM – nocturia past 3 months
What factors are likely to have contributed to the current prob?
• Soft drink consumption – drinking 1.5L coke daily
What lab tests should the admitting dr request?
• Glucose, renal function, osmolality, ketones, acid-base

3. BP 95/65, pulse 90/min, mouth an dtongue v dry and skin turger reduced – JVP was low – drowsy but could answer questions – following results –
Glucose 76mmol/L (<7.0)
Urea 14.8 (<8)
Creatinine 0.19 (0.11)
Osmolality 365mosm/kg (275-285)
3OH Butyrate 1500 umol/L (<200) – hydroxybutyrate
Bicarbonate 22 mmol/L (20-27)
Arterial pH 7.34 (7.36-7.44)
Urine ketones negative
How are these findings interpreted?
• Severely hypovolaemic
How do you interpret the lab results?
• Severe hyperglycemia, high osmolality, prerenal failure, not ketoacidotic
What tx should be started?
• IV saline, insulin infusion, be careful of K levels
What clinical and biochem measures should be monitored?
• Conscious level, BP, pulse, urine output, glucose, K

4. Tx w IV fluids and a continuous IV insulin infusion w excellent clinical improvement and rapid control blood glucose – insulin discontinued but within 1 day blood sugar had risen from 7 to 17 mmol/L – antidiabetic drug metformin was given but failed to adequately control blood sugar – discharged from hospital after 6 days taking twice daily pre-mixed insulin injections – seen by dietician
What did the dietician advise him?
• Low fat diet, complex carbs
What did the diabetes nurse specialist discuss w him?
• Self monitoring of bld glucose, insulin administration, recog and mgt of hypoglycemia
What sort of diabetes is this? Will he need to stay on insulin indefinitely?
• This is type 11 DM
How does metformin work?
• ↑ sensitivity of tissues to insulin action

Case 2 – Early onset Type 2 DM + insulin induced hypoglycemia

1. 24F Indian – presenting w inflame and intense itching around vulval area – doctor checked blood glucose to be safe – 15.6 mmol/L
What other sx would you like to enquire about?
• Thirst, polydipsia, polyuria, nocturia, fatigue
What is the cause of pts complaint?
• Vaginal candidiasis (M = balanitis)
What info from the hx and exam would help you decide what sort of DM this is?
• Family hx (both parents Type 11 DM onset in their late 30s, mother died of diabetic kidney dis – weight 60Kg, BMI 23.5 – acanthosis nigricans absent
Are there any lab tests that can help you decide?
• Anti-GAD antibodies - negative

2. DM managed w sulfonylurea drug glibenclamide for 2 yrs until pregnant aged 26 – glibenclamide then stopped and she started insulin tx – pregnancy had a good outcome and pt continued insulin twice daily after delivery – 5 yrs later (age 31) wants to have another baby – her total insulin dose was 52 U/D but her capillary blood sugars high (15mmol/L) – HbA1c 10.8%
how do sulfonylurea drugs work?
• Opening K channels which allows Ca2+ into B cells – stimulating insulin secretion
What sort of DM does she have?
• Early onset Type 2 DM
What is HbA1c – and what does it measure?
• Glycated hemoglobin – medium-term glycemic control
Why is it impt to have good blood sugars before conception?
• Hyperglycemia is teratogenic

3. Pt changed to 4 times daily insulin and total dose 84 U/D – 6 months later, HbA1c down to 6.4% but now experiencing episodes around 1 am involving sweating and feeling v hungry and had gained 5Kg weight
what are these nocturnal epidsodes – what is their physiology?
• Hypoglycemia – counterregulatory hormone release of adrenaline
How should this prob be managed?
• Determine time of episodes – reduce appropriate insulin dose, bedtime snack
What accounts for the weight gain?
• Improved glucose utilization, cessation of gluconeogenesis, the reverse of weight loss with poor glycemic control
What complications can start to develop after 7 yrs DM – how do we check to see if they are developing?
• Retinopathy, nephropathy, neuropathy → retinal screening, visual acuity, blood pres and albuminuria, clinical examination of feet

Case 3 – Type 1 DM disguised as Secondary DM

1. 33 M European origin – referred to gastro clinic w 12 month hx bloody diarrhea, abdo pain, tiredness and weight loss – 65→59 Kg – a colonoscopy showed extensive ulcerative colitis – sx deteriorated and admitted to hospital – IV hydrocoritisone started and as sx started to develop was switched to oral prednisone – after 2 wks, discharged but soon began experiencing polyuria, ↑ leathargy and blurred vision – blood glucose was 27.6 mmol/L
What sort of drugs are hydrocortisone and prednisone? What effects do they have on glucose metab?
• Glucocorticoids - ↑ insulin resistance, post receptor
What additional hx and lab tests would be helpful?
• Family hx negative – previous sx or blood tests (none) – urine ketones (only 1+), bicarbonate normal 29 (24-30), creatinine 0,09 (normal), HbA1c (10.2%), islet cells antibodies negative
How should his DM be managed?
• IV fluids and continuous IV insulin infusion followed by s.c. insulin
What sort of DM is he likely to have?
• Debatable – no phenotypic feats of type 2 DM, type 1 possible, steroid induce diabetes?

2. Tx initially w IV fluids and IV insulin infusion – discharged on twice daily premixed insulin (30U/D) – when seen 3 months later, the prednisone had been stopped and he was getting a lot of hypoglycemia episodes which continued to occur despite reductions in insulin dose – after a further 9 months, he stopped insulin – at that time, he weighed 64 kg, and his blood glucose ranged from 5-7 mmol/L – after 3 months off insulin, his colitis relapsed and prednisone restarted – blood sugars soon became raised again
How was he able to come off insulin?
• ↓ in insulin resistance – whatever insulin secretory capacity he has now is adequate to control blood sugar
Are there any lab tests that could confirm what type of DM he has?
• Anti-GAD antibodies – 209 units (normal <10)
Is he likely to need insulin permanently?
• Depends on his type of DM – this looks like type 1 - honeymoon phase
How would you manage his DM in the future if his colitis relapsed?
• yes

DIABETES – DEFINTION, CLASSIFICATION AND PATHOPHYSIOLOGY

PHYSIOLOGY

Insulin – hormone secreted by b-cells islets of langerhans → promotes glucose utilisation, protein synthesis and the formation/storage of lipids
Glucagon – hormone secreted by islet a-cells → ↑ glycogenolysis, ↓ gastric motlity, ↓ gastric and pancreatic secretions, ↑ urinary excretion N2 and K

DEFINTION

A syndrome of pathologically elevated blood glucose (hyperglycemia) assoc w an abnormality of the secretion or action of insulin and a tendency to chr vascular complications.

Diagnositc Criteria
Normal Impaired Diabetes
Fasting <6 6-6.9 ≥7
2 hour <7.8 7.8-11 ≥11.1
Sx pts → one dx bld gluc test
Asx pts → 2 dx bld gluc tests
Note – be cautious with IGT patients with factors that may temporarily worsen glucose tol (eg intercurrent inf, thiazide or diuretic use) – check 3-6 wks post resol
oGTT only reqd if uncertainty about dx (≈10%)
IGT develops into DM ≈25% of cases


CLASSIFICATION

Type 1 Immune-mediated B cell destr, Idiopathic
Type 2 Obesity related, insulin resis
Genetic AD (MODY), mitochondrial
Pancreatic dis Pancreatitis, Pancreatectomy, CF, Hemochromatosis
Endocrinopathies Acromegaly, Pheochromocytoma, Cushings
Drugs Glucocorticoids, Tacrolimus
Gestational Onset or first recog in preg (requires post partum classification)
Note - 2˚ DM if not T1 or T2 (≈2%)

TIDM PATHOPHYSIOLOGY

Type 1A Immune-mediated
Cell-mediated autoimm destr islet B cells
Genetic predis Strongest link w HLA DR/DQ region Chr 6 (some DQ alleles confer susceptibility, others are protective)
↑ risk if 1st degree relative w T1DM ( ¬3-6%)
High concordance identical twins (30-50%)
Assoc w other autoimm diseases – hypothyroidism, graves, PA, addison’s, celiac, vitiligo, m.gravis)
Abnormal activation of cell mediated imm sys leads to –
Inflammatory response within islets (insulitis)
Humoral response – prodn of antibodies to B cell antigens – islet cell Ab, insulin Ab, anti-IA2, anti-GAD)
Etal triggers – international variability in incidence → ?viral, ?dietary
Pre-diabetic phase w islet cell destr but preserved glucose tol
Rate of b-cell destr variable (faster in younger subjects, slower in adults w assoc autoimm dis LADA)
Continuing b-cell destr → progressive loss insulin secretory reserve
Later stages → no insulin secr → ketoacidosis prone, exogenous insulin reqd for survival

Type 1B Idiopathic
↑ incidence Africans/Asians
Insulinopenia and prone to ketoacidosis but no autoimm evidence
Episodic ketoacidosis and varying degrees of insulin deficiency betw episodes
Strongly inherited

Type 1 DM Epidemiology
Highest prevalence developed nations
Considerable variability betw countries
Incidence ↑ in developed countries

FHx ↑ lifetime risk from 0.4% to 3-6%

T2DM PATHOPHYSIOLOGY

Insulin resistance and relative insulin deficiency
Strong rship to truncal obesity and other components of metabolic syndr
Insulin resis at all levels (liver, fat, mus)
Genetic factors → 5-10x ↑ risk in 1st degree relatives, 40% lifetime risk if affected parent, 70% if both, MZ twin concordance 80-90%
Epidem 9% Maori, 7.5% PI, 2.8% other
Insulin resistance
↑ visceral fat = ↑ TGs → large adipocytes
Large adipocytes resisitant to insulin tyring to suppress lypolysis → ↑ lipolysis leads to ↑ release non-esterfied fatty acids (NEFA) and glycerol
NEFA + glycerol + inflammatory CKs released by visceral adipose tis (eg TNFa, IL6) aggravate insulin resis in mus and liver
Adiponectin +/- resistin – may provide the link betw truncal obesity and insulin resis
Adiponetin downregulated in obesity → ↓ concentrations assoc w ↑ risk T2DM
Resistin secreted by adipocytes of obese mice → ↓ adipocyte glucose uptake
In insulin resistant states, insulin signalling is blocked by inhibition of tyrosine phosphorylation of IRS proteins (disruption of IRS-2 gene in mice → ↑ insulin resis)
Obesogenic evt - ↑ availability/marketing high calorie foods, ↓ home meal prep, ↑ TV/computer use, ↑ use motorised tport, ↓ school PE, ↓ physical labor

Metabolic Syndrome
Pathophysiology
Excess energy intake and ↓ physical acitivty +/- (?Fetal programming + ? Genetic predisposition) → Truncal obesity and insulin resistance
→ 1. glucose intolerance (T2DM) 2. HT, 3. Dyslipidemia, 4. Endothelial dysfunction (inflammatory markers and procoagulant state)
Epidem 25% of adults
Ckassif Central obesity (waist >94cm M / >80 cm F) AND two of a. TG >1.7, b. HDL <1.03 M / <1.29 F, BP >130/85, T2DM or IFG (>6)
Fetal programming (Barker Hypothesis)
Poor nutrition + placental insufficiency + fetal metabolic defects → fetal malnutrition → modified metabolic pways → predis for metabolic syndr

T2DM = progressive d/o (5-6% of pts go on to insulin tx each yr)
Progressive islet cell dysfunction
b-cell mass falls → ineffective control of excessive postprandial glucagons release from a-cells

Maturity onset diabetes of the young (MODY)
Mongenic DM - Inheritance consistent w AD
Young age onset (<25 yrs)
Not ketosis-prone and Not dependent on exogenous insulin for survival
Often normal weight
Thought to a/c for 1-5% of all DM in European countries

DIABETES – PRESENTATION AND CLINICAL PHENOTYPE


Sxs
1. Polyria
2. Polydipsia (excessive thirst)
3. Weight loss
4. Fatigue
5. Blurred vision
But 50% of pts w DM are asx

Phenotypical Summary
• T1DM – IDDM – 10%
• T2 DM – NIDDM – 90%

Type 1 Type 2
1. Age of onset Young and <40 yrs Older and >50 years
2. BMI <26 >30
3. FHx Negative Positive
4. Ethnicity European M/PI/E
5. DKA Likely (90%) Rare
6. Prominent sxs Yes Usually no
7. Retinopathy at dx No Maybe (suggestive of longstanding DM – ie 5 yrs)
8. Blood glucose 2-25, Variable Stable
9. Withdraw insulin Abrupt ↑ glucose Gradual ↑ glucose
10. Anti-GAD antibodies Positive Negative

BMI - T2DM Mechanism
• ↑ adiposity causes insulin resistance at sites of skeletal mus and other key sites
• recently discovered proteins exclusively from adipose tissue (adipokines → Resistin and Adiponectin) – may provide the link betw obesity and T2DM

F.Hx - Genetics
• If one parent has T2DM → child’s lifetime risk is 50%
• Most pts w T1DM → no f.hx T1DM
• MODY = T2DM <25y and f.hx positive → monogenetic cause for diabetes (rare)

Ethnicity
• M/PI - ↑ prev T2DM
• Caucasian - ↑ prev T1DM

Diabetic ketoacidosis (DKA)
• 90% of pts developing DKA (↑ glucose, pH <7.35, ↑ ketones) → T1DM
• Diabetic sxs plus
• Metabolic acidosis
• Kussmaul breathing (hyperventilation)
• N/V (dehydration/gastropariesis)
• Abdo pain
• Confusion, stupor, coma
• Acetone breath
• Ketone bodies - B-hydroxybutyrate, Acetone, Acetoacetate

Antibodies
• Antibodies to GAD and IA2

HYPERTHYROIDISM


Thyrotoxicosis Clinical condition caused by ↑ levels of circulating thyroid hormones

Etiology
1. Diffuse toxic goitre (Graves dis) – 85%
2. Toxic multinodular goitre
3. Toxic nodular goitre (Plummer’s dis)
3. Toxic adenoma (Hot nodule) – solitary toxic nodule, benign neoplasm
4. Subacute thyroditis (De quervains or viral thyroiditis)
5. Drugs – amiodarone, iodides/contrast media, lithium, thyroxine, interferon-a
6. Pregnancy – HCG is a weak thyroid stimulator → mild transient hyperthyroidism during pregnancy

Graves Disease
Autoimmune – IgG antibody stimulates TSH R
Prevalance 1%
F>M 8>1
Triad 1. Thyrotoxicosis (spontaneous remission in 25%)
2. Diffuse goitre with bruit
3. Proptosis (eyes pushed forward by extra-ocular triad)

Subacute Thyroiditis (Pain + Fever + Fatigue + Thyrotoxicity + Short duration)
Painful thyroid gland inflammation, Tender thyroid/neck radiating to ears
Unknown etiology - ?viral
Acute phase proteins and ESR ↑
Biochemical hyperthyroid → hypothyroid phase → recovery 3-5 months
Scintiscan shows absent isotope trapping
Glucocorticoids v effective at relieving sxs

Sxs
Weight loss
Tremor
Muscle weakness
↑ apetite
Frequent bowel motions
Palpitations
Fatigue
Heat intolerance/↑ sweating
Nervousness

Signs
Goitre
Tachycardia
Onycholysis (nail dystrophy in chronic hyperthyroidism of any cause)
AF → risk of thromboembolism (stroke)
Tremor
Proximal muscle weakness and wasting
HF
↑ pp – hot/sweaty causing vasodilation depressing diastolic pres + thyroxine ionotrope causing ↑ systolic pres
Thyroid bruit (graves only)
Prominent eyes (proptosis/exopthalmos) - (graves only)

Ixs
1. TFT a. ↓ Serum TSH (below detection limit - <0.004 mU/l) – normal or detectable TSH excludes thyrotoxicosis in 99%
Reduced TSH (0.004-0.4 → caused by goitre, glucocorticoids or sickness)
b. ↑ serum T3/T$
2. Disease type markers
a. Thyroid peroxidase antibody (TPO) = thyroid microsomal antibody → normal is negative, positive in graves (80%) and hashimotos (95%)
TSH R antibodies not measured routinely
b. Thyroid gland isotope trapping rate → normal <2% 20mins post IV pertechnetate - graves 5-20% with diffuse uptake, subacute thyroiditis 0%
3. Thyroid scintiscan
pertechnetate anion competes with iodide, trapping rate related to T4 output
pattern indicates function and is a guide to thyroid size and shape, but inf to US
↑ trapping in graves or TNG, absent in subacute thyroiditis,

Tx
1. Anti-thyroid drugs (thionamides)
a. Carbimzole (CBZ) - 15 mg bd then 15 mg od
b. Propythiouracil (PTU) - 150 mg bd then 150 mg od (preferred in pregnancy as rare teretogenecity in CBZ)
Block enzymes responsible for iodide organification and coupling
↓ T4/T3 stroes in 2-6 wks
Used either ST 6-12 wks prior to surgery or a one year course with hope for remission (30%)
S.Eff Minor – macular rash, urticaria
Major – agranulocytosis (medical attn required if sore throat or fever)
2. Complementary Tx
a. B-blockers – relieve palpitations, anxiety, insomnia in minority until euthyroid or while radioiodine working.
b. Iodides (rare) – used always after antithyroid drugs have blocked the gland (Lugol’s iodine 1ml bd)
in pharm does, block proteolysis and release of thyroid hormones and organification but escape occurs after one week
used in severe thyrotoxicosis for rapid effect or to prepare for thyroid surgery to reduce gl vascularity
c. AF control – 50% remission when return to euthyroid
3. Radioacitve iodine (most common) – 131 iodine (outpatient)
Effective as single dose in 80-90% within 6-12 weeks
No ↑ risk thyroid or extra-thyroidal ca (50 yr FUP)
Avoid preg for 3 months
Use in adults over 20 yrs
Hypothyroidism occurs in 75% within one year, but lifetime risk continues persists
4. Subtotal Thyroidectomy (rare)
Removal of 5/6 gl allows remission but risk of recurrent thyrotoxicosis, hypothyroidism and recurrent laryngeal n palsy

HYPOTHYROIDISM


Epidem
F>M
↑ incid w age

Etiology (1’ Hypothyroidism)
1. Autoimmune dis (hashimotos) – most common developed world
2. Iatrogenic – thyroidectomy, radioactive iodine or external radiation therapy for head and neck ca
3. Drugs – lithium, amiodarone, interferon-a
4. Iodine defieincy – (endemic goitre)

Hashimotos Thyroiditis
Cell and antibody mediated destr thyroid tis
2 forms – goitrous and atrophic
Almost all pts have serum antibodies to thyroglobulin (TG), thyroid peroxidase enzyme (TPO) and antibodies that block binding binding of TSH to R
Assoc w other autoimm conditions – eg PA, Addisons

Sxs
Non-specific and Protean (variable)
*Tiredness/malaise
*Weight gain
*Cold intolerance
*Goitre
Constipation
Puffy eyes
Dry coarse skin
Poor memory
Depression
Poor libido
Dry brittle unmanageable hair/hair loss
Menorrhagia or oliomenorrhea
Myopathy
Psycosis
Coma

Signs
*Mental slowness
*Dry thin hair
Dry skin
Hypothermia
Heart failure
*Bradycardia
Cold peripheries
Edema
*Periorbital edema - ?(Myxoedema – accumulation of mucopolysaccharide in subcut tis)
Goitre
Overweight/obesity
Proximal myopathy
*Slow relaxing reflexes

Ixs
1. TFT Elev serum TSH (earliest sign)
Fall in T4 followed by fall in T3
Subnormal T4 in the absence of elevated TSH implies 2’ hypothyroidism (ie a pituitary problem) – specialist ix reqd
Patients w severe illness can have “sick euthyroidism” – subnormal T3 and normal TSH which recovers once they get better
2. A-bod Thyroid antibodies +ve (if autoimmune)
3. Bloods Severe hypothyroidism – hyponatremia (↑ ADH + impaired clearance free water), elevated CK (myopathy), elevated serum chol
4. Thyroid US +/- doppler flow assessment (solid, cystic or complex nodule)
5. Thyroid scintiscan (99m Technecium)
6. CXR +/- thoracic inlet views
7. Thyroid cytology – FN biopsy all solitary nodules >1cm + poss dominant nodules also (US guidabce may be reqd for complex nodules ie solid/cystic)

Tx
Thyroxine – 0.1-0.15 mg/day for life (dosage determined by TFTs) – aim to normalise all three indices but TSH normalisation most critical
T4 half life approx one week – may take up to 6 wks for TFTs to stabilise after a dose change

Myxoedema Coma
Severe hypothyrodism presenting with confusion and coma (esp in elderly).
Typical feats – hypothermia, cardiac failure, hypoventilation, hypoglycaemia, hyponatremia.

Myxoedema Madness
Depression is common but occasionally w severe hypothyroidism in the elderly patient → frank dementia or psychosis w delusions.

MACROVASCULAR COMPLICATIONS

a. Epidemiology of CVD and DM
Absolute risk – 2-4x ↑ (T1 and 2)

CVD responsible for 75% of diabetic hosp admissions or deaths
Risk esp high when overt nephropathy (>300 mg/albumin/24 hr)
Lipids,smoking, HT do not a/c for excess risk in these pts

b. Clinical presentation
1. IHD – 2-4x ↑ prevalence, diabetic pts poorer prognosis following MI, more extensive and more distal coronary art dis
2. HF – due to ↑ incid of HT and IHD (more silent MIs)
3. Stroke – 2x↑ prev, survival worse
4. PVD – 4x↑ prev, propensity for distal atherosclerosis, prox dis also ↑, physical signs – carotid/femoral bruits, loss of foot pulses
Management
• Mgt of those presenting with ACS, stroke or HF are similar to mgt of non-diabetic pts with some exceptions
• Use glucose-insulin-potassium infusions in post MI period (even if no diabetes and blood glucose >11 mmol/l??

c. Causal Factors – Hyperglycemia, BP, Lipids

d. Risk Factor Modification
1. Glycaemic control (HbA1c <7%) - reduction appears to be more effective for microvascular dis, it is not clear whether glucose per se or the
cluster of associated metabolic syndrome risk factors or the genetic or behavioural characteristics assoc w metabolic syndr are responsible for the incr CV risk
2. BP control (<130/80) – for any given BP, CV risk 3x ↑ in diabetic pts – first line ACEI then others
3. LDL <2.5 (or even <1.6), TG <1.7, HDL >1 – for any given total chol, CV risk 4x ↑ in diabetics → statin therapy regardless of baseline chol
4. Aspirin
5. Smoking cessation

Key Points
• DM pts 2-4x ↑ CV risk
• Most will die of CVD
• Hyperglycemia is related to macrovascular dis risk in T1 and T2
• Nephropathy substantially ↑ CV risk
• DM worsens prog in AMI, HF and Stroke
• BP and lipids should be aggr tx
• Multiple CV RF intervention effective

DIABETES – MICROVASCULAR COMPLICATIONS; NEPHROPATHY AND HYPERTENSION


Microvascular – 1. Retinopathy, 2. Nephropathy, 3. Neuropathy
Macrovascular – 1. Cerebrovascular dis, 2. IHD, 3. PVD

Microvascular Complications
• T2DM patients may already have these complications at dx of DM because they can remain undx for long periods
• Main determinants for the development of microvascular complications are duration of DM and glycemic control

1. Retinopathy

• 5+ yrs to develop
a. Early stages micro-aneurysms (dots), small circ hemorrhages (blots) +/- exudates classified as b/ground retinopathy of varying severity (not sight thr)
b. Deteriorating stage pre-proliferative retinopathy characterised by flame-shaped hemorrhages, venous tortuosity + cotton wool spots
c. Advanced stages devt new retinal vessels, proliferative retinopathy, sight threatening, vitreous hemorrhage can cause retinal detachment w perm sight loss
Detection Axs until v advanced → diabetic pts should be screened for eye dis at regular intervals (2 yearly)
Pts w known eye dis should be under ophthalmogical supervision
Tx Good glycemic control prevents devt and progression
Laser therapy for pre-proliferative and proliferative retinopathy prevents blindness (Complications - loss of peripheral and night vision)
Other procedures – eg vitrectomy
BP reduction and smoking cessation

2. Neuropathy

Nat hx Periph neuropathy most common manifestation (Predominantly sensory affecting feet and legs)
Early stages – asx or symptomatic (dysaesthesia, paraesthesia)
Late stages – anesthetic feet prone to ulceration and or pressure areas
Advanced stages – neuropathic (charcot) joints, recurrent ulceration, neuropathy of hands
Autonomic neuropathy
Most common – erectile dysfunction
Advanced dis – gastroparesis, diarrhea, neurogenic bladder, postural hypotension
Detection Sensation testing – vibration, pressure and lost ankle reflexes
Tx Good glycaemic control
Education and podiatry services for pts w at risk feet
Tx of co-existing PVD
Ulceration – non-weight bearing, antibiotics, surgery to remove necrotic/infected tis, glycaemic control

3. Diabetic Nephropathy

Path - Basement membr thickening + mesengial expansion → glomeruli become sclerosed and obliterated (later stages)
Nat hx
• 10-20 yrs
• Defining clinical and lab findings – 1. BP, 2. Albuminuria, 3. Renal function (eGFR)

Stage → Normal Incipient Established Advanced
1. BP Normal for age Raised + Raised ++ Raised +++
2. Albuminuria (mg/day) or Albumin/Creatinine ratio (mg/mmol) <30
<3 30-300 (microalbuminuria)
3-30 300-3000 (macroalbuminuria)
30-300 >3000 (nephrotic range)

3. GFR (ml/min) Normal or ↑ for age Normal or ↑ for age Declining (≈1ml/min/month) <15 (end stage uraemia)
Once stage of ↓ GFR reached → progression to end stage renal failure is inevitable w/o tx
Vicious cycle where HT causes further glomerular damage which in turn worsens the HT
Control of HT will arrest/slow progression of nephropathy

Prenvention
• Maintainence of good glycemic control (measure via HbA1c)
Tx
• ACEI/ARB → ↓ albuminuria and preserve renal function over and above their hypertensive effects (1st line tx for diabetic nephropathy)
• Other anti-hypertensives

HT in T2DM
• Extremely common as most have the metabolic syndrome (glucose intol + HT + dyslipidemia + endothelial cell dysfunction + abdominal obesity)
• All these factors (+ smoking) → sig RFs for CV dis → main cause of premature morbidity in this popn
• ↓ HT → ↓ CV risk
• End-stage chronic RF assoc w –
High rates of CV dis – stroke, TIA, angina, MI, HF, claudication, gangrene
Advanced microvascular complications – visual loss, blindness, foot ulceration, bladder, gastric problems

Hypertensive Nephropathy
• Chr HT = leading cause of Chr RF and presents similarly to diabetic nephropathy w HT, progressively worsening albuminuria, ↓ RF and inactive urine sediment (ie no casts or red cells in MSU)
• Can be difficult to say whether diabetic or hypertensive nephropathy is the dominant cause, but est nephropathy (in absence of diabetic retinopathy) suggestive of HT
• Principles of mgt of both diabetic and hypertensive nephropathy are the same

Hypertension Tx
• Aggr tx = ↓renal func decline AND ↓ CV risk
• Target BP - 130/80
• Sequential anti-hypertensive drug use
1. ACEI or ARB (first line) – ?combined ACEI/ARB
2. + diuretic (thiazide or frusemide)
3. + CCB (felodipine)
4. + b-blocker
5. + a-blocker
Problems
• Inadequate dosage – aim to get ACEI/ARB to maximum
• Failure to reach target BP – 2+ agents may be reqd
• Hyperkalemia concerns – ACEI/ARB both K-sparing and ↑ K w ↓ GFR → ↑ plasma K (counteract with K-losing diuretics – frusemide, thiazides)
• Avoid K sparing diuretics – spironolactone, amiloride
• Renal function concerns – ACEI/ARB → sig ↓ in GFR when first started (due to impaired renal autoregulation) – continue anyway
• Renovascular dis concerns – a large ↓ in GFR above → consider renal artery stenosis (only assess pts w >33% ↓ from baseline GFR for renal art dis)

Non-progressive microalbuminuria
• Microalbuminuria does not specifically indicate diabetic +/- hypertensive nephropathy
• Low level non-progressive or intermittent microalbuminuria can be seen with –
Episodes of poor glycemic control
After unusual exercise
Post-partum
Manifestation of endothelial dysfunction

Other common complications of diabetes
a. Mononeuropathies – usu recover (incl femoral neuropathy), CN3 and 6 palsies
b. Cataracts
c. Cutaneous/Subcutaneous – ↑ infections (cellulites, UTI, candida), carpal tunnel, trigger finger,

DIABETES TUTORIAL – INSULIN

1. Insulin Injection
a. Subcutaneous
b. Not muscle – incr vascularity leads to faster absorption
2. Sites
a. Abdo
b. Thigh (slower uptake than abdo)
c. Rotate injection sites to avoid lipohypertrophy (results in variable absorption)
3. Technique
a. Pinch up fat
b. Inject at 90 degr
c. Disposal in hardened plastic container
d. Side effects – minor bleeding from subcut veins
4. Methods
a. Syringe – can re-use for ~3 days
b. Penmix
5. HbA1c
a. Proportion of Hb that is glycocylated
b. Normal = 4-6%
c. 3/12 of glycaemic control
d. Measure every 3x months (life of a rbc)
e. All outcome trials on diabetes tx done using HbA1c
f. T1DM → ideal HbA1c = 6.5-7% (reduced microvascular complications while minimising hypogly risk – see graph)
g. Hypoglycemic risk less of a concern in T2DM pts so you can tx these pts more aggressively
6. Microvascular complications
a. Nephropathy
b. Retinopathy
c. Neuropathy

Case
65 M - T2DM for 15 yrs
HbA1c remains 8.9% despite sensible diet + exercise
BG readings generally in double figures and feels tired
Current regime – Metformin 850 mg daily, Gliclazide 160 mg daily, Cannot afford thiazolidinediones

1. Thiazolinediones (TZD) = Glitazones
d. PPARa Agonist – muscle, liver, fat
e. Insulin sensitisers
f. Side effects – 1. CHF, 2. ↑ risk MI, 3. ↑ # risk (controversial)
2. Acarbose
g. ↓ b/down of carbs → slower carb absorption
h. Inhibits enzyme “glucosidase”
i. S.eff → abdo distension, flatulence etc
j. Only ↓ HbA1c by 0.5% so used less when side effects are severe
3. Metformin
a. Max dose – 3g / day
4. Sulphonylurea (Gliclazide)
a. Max dose – 160 mg / day

Insulin
Starting insulin – when on 2x oral drugs at max dose and not well controlled
Outpatients – start on 0.1-0.2 U/kg per day (more aggressive if in hospital)
1. T2DM Patient Regimes
b. Start Protaphane – eg 80kg man = 8U/day
i. Given at bedtime – due to 3-4am spike of cortisol, adrenaline, glucagons, GH → elevated blood glucose
ii. “fasting hyperglycemia”
iii. Allows waking up with normal BG
c. ↑ Protaphane every 3 days by 10% until normal BG (fasting 4-7)
d. Stop sulphonylurea – if stopped immediately when starting insulin, pt will be prone to hyperglycaemia
e. Continue metformin – helps with weight reduction and limits insulin requirements
f. If 50 U / day and BG control still ineffective → Insulin bd
i. Typically penmix 30
ii. Before breakfast and before dinner
iii. Do not take before bedtime (as penmix contains actrapid)
g. Problems with Insulin
i. Weight gain occurs when starting insulin
ii. Hypoglycaemia
2. T1DM Patient Regimes
h. Pts v sensitive to insulin (cf T2DM pts w insulin resistance)
i. Basal Bolus Routine
i. Basal insulin → Protaphane (or Humulin N) - bd
ii. Bolus insulin → Novorapid (or Humalog) – 3x daily before meals
j. Lantus (glargine) → 1x fewer injections reqd – only 1x baseline injection / day reqd
k. Insulin pumps
i. Subcut → pump on program
ii. Only novorapid/humalog
iii. More physiologically correct
iv. Very expensive
v. Very effective for dawn phenomenon (ie waking up with high BG)
vi. Very effective for pts w many hypoglys
3. Recording BG
l. Columns – before and after each meals
m. Rows – days
n. Scan for patterns
4. Adjusting Insulin
o. Consider weight – dose v dependent on weight esp T2DM pts , adjust by 6 or 12 U boluses?
p. ISF (insulin sensitivity factor) – useful esp for T1DM pts
i. = 100 / TDD (total daily dose of all insulin)
ii. Eg 100/50 units = 2
iii. Therefore – for every 1 unit of insulin, you ↓ BG by 2 mmol/L
q. Ø ∆ doses by >10%
r. Ø more freq than every 3 days

Case
How do you start pt on insulin?
• Start insulin when 2x oral meds to max dose + ineffective control
• Protaphane before bedtime (0.1 U / kg) – adjust every 3 days by 10% until BG 4-7
• Ø Glicalizde after 3 days
• ↑ Metformin dose to max
• If still ineffective at 50 U day → change to penmix 30 etc and start bd regime before breakfast and dinner
• Side effects – weight gain, hypos

Insulin and Duration of Action
• Ultra short acting – Novorapid, Humalog
• Short acting – Actrapid, Humulin R
• Intermediate acting – Protophane, Humulin N
• Humulin 30/70, Penmix 30 (lower number = SA insulin); Actrapid30/Protophane70
• Insulin glargine (Lantis) – background insulin, no peak, ↓ overnight risk of hypogly
Practical Issues
• Can interchange betw brands w/o probs
• Structural modifications allow altered kinesthetics – only applies to subcut insulin, not venous insulin
• Problems – postprandial hypergly (1-2 hrs after meal) or delayed post-prandial hypogly (3-6 hrs after meal)

TUTORIAL – DIABETES – DKA, IVI INSULIN, HYPOGLYCAEMIA

Case 1 - DKA

17 M European
PC – exhaustion, weight loss 6kg, excessive thirst, polyuria, nocturia 2/52
Over 24 hrs prior to admission – difficulty waking from sleep, vomitus on pillow
O/E – Bp 65/40, PR 100, JVP v low, Skin turgor reduced, kussmaul respiration
Biochem – Na 142, K 6.1 ↑. Creat 0.21, HCO3- 3, ph 6.91, BG 36.2, Urine ketones +++

1. Dx → DKA
a. Metabolic acidosis and is in ARF with hyperkalemia
2. Management
a. Fluids → aggressive tx normal saline
i. 2L in first hour – then reassess
ii. Likely to require 4-6L over 24 hrs
b. Elytes → freq Na and K measurements
i. Total body Na and K deficient (H+ into cell, K+ pumped out thus hyperkalemia)
ii. Expect rapid ↓ in K as acidosis clears and insulin started
iii. Don’t give KCl with initial stat fluid bag, wait to first fluid bolus given then assess K requirement
c. Insulin
i. IVI Insulin 10-15 U Actrapid
ii. Subcut if no IV access
iii. Aim for smooth decline in sugars over 24 hrs
d. Bladder catheter – urine quantity measurement
e. +/- NG Tube – vomiting due to gastric paresis and assessing fluid bal
f. CVP line – probably reqd, helpful assessing fluid bal in difficult situations
g. Intubation – may be reqd if GCS low
3. Clinical and biochem measures to follow during initial tx period
a. Clinical → BP, pulse, GCS, U/O
i. Hourly
b. Biochem → Na, K, Glucose, Creatinine, Urea, consider ABGs or serum bicarb
i. Every 1-2 hrs initially then less depending on progress
ii. 4x measurements in 1st 24 hrs appropriate
4. Changing pt to a subcut insulin regime
a. When pt is alert, awake and able to eat
b. Try switching to subcut in morning rather than at night
c. Commence basal insulin and give Novorapid + keep IVI insulin going for at least 2 more hours to ensure adequate overlap
d. Use body weight and insulin requirements in past 24 hrs as a guide to starting tx
e. 0.5 U per kg/day for T1DM (cf 1-1.5 U per kg/day in T2DM)

Case 2 – HONK

72 M
PC – excessive thirst, polyuria, nocturia 2/52
Borderline DM 5 yrs prior
Intense thirst being quenched w coke 3L/day
Evening prior to admis → felt v sleepy, went to bed early, difficult to wake and confused the next morning
O/E – BP 110/60, PR 95, JVP v low, Skin turgor ↓, tongue dry
Biochem – Na 165 ↑, K 5.7 ↑, Creat 0.23, HCO3 19, pH 7.38, BG 72.4, urine ketones +

HONK
1. Defintion
a. Severe hypergly develops w/o sig ketosis
b. Metabolic emergency due to uncontrolled T2DM
c. Often precipitated by consumption of glucose-rich fluids, concomitant meds such as thiazides or steroids or by intercurrent illness
d. Characterised by hypernatremia and profound BG ↑ (causing hyperosmolarity) and a normal pH
2. Clinical Feats
a. Endogenous insulin levels ↓ but still sufficient to inhibit hepatic ketogenesis
b. Meanwhile, glucose prodn is unrestrained
c. Presentation
i. Profound dehydration (2ndry to osmotic diuresis) – preferential water excr
ii. ↓ LOC (directly related to elev of plasma osm)
3. Management
a. Ixs + Tx the same as for DKA except -
b. Hyper-osmolar state predisposes to stroke, MI and arterial thrombosis (main causes of mortality) → prophylactic subcut heparin
4. Prognosis
a. Mortality rate 20-30%
b. Mainly due to adv age of pts and freq of intercurrent illness
c. Unlike DKA, HONK is not an absolute indication for subseq insulin therapy
d. Survivors may do well on diet and oral therapy

Case
1. Seeking sweat drinks to quench thirst is common as hyperglycaemia induces alteration in taste
2. Coke has 10g per 100 ml
3. Management
a. ½ N saline (due to hypernatremia) – may require 6-8 L (Note that N saline will be hypotonic to current state)
b. Clexane
4. Taking pt off insulin
a. Similar to DKA
b. Probably use penmix 30 as insulin of first choice once normoglycaemic and E+D

Case 3 – Insulin induced hypoglycemia

25 F
T1Dm of 19 yrs duration
Admitted to hosp following MVA
She is unconscious, Ø obvious injuries, Ø focal neurological signs, BG 0.9 mmol/L

1. Dx → insulin-induced hypoglycaemia
2. Impt counter-regulation hormones to hypogly
a. Adr, Nor-adr
b. Glucagon
c. Cortisol
d. GH
3. Immediate management
a. ABC + 5 ml 50% dextrose IVI
b. Then 10% IVI dextrose
c. Oral CHO when awake
4. What info would you seek from pt when they regain consciousness
a. Freq of hypos
b. HbA1c
c. Co-existing hypothyroidism, addisons, insulin error, deliberate overdose, eating habits
5. Hypoglycaemic unawareness
a. Autonomic threshold is lowered below cogv awareness (part of autonomic neuropathy)
b. Assoc w either long standing T1Dm or recurrent hypos
c. Can be partially/fuly reversible if strict avoidance of hypos for 3x months
6. Advice on management
a. Mild – take 3x dextrose tablet or glass OJ and follow w blood test after 5 mins, then have something to eat
b. Severe – if unconscious, lie on side, try IMI glucagon, if no rapid response dial 111
c. Partner should know how to deal with situation
d. Avoid driving until hypos controlled

Case 4 – Sulphonylurea induced hypoglycaemia

72 F
T2DM 12 yrs duration
Admitted with collapse
Taking Glibenclamide 10mg bd
BG 1.3, plasma Creatinine 0.19?

Creatinine Reference Ranges
• 1 mg/dL = 88 umol/L
• Female normal → 0.5-1 mg/dl = 45-90 umol/l
• Male normal → 0.7-1.2 mg/dl = 60-110 umol/l

1. Immediate management
a. ABC + 100 ml 10% dextrose
b. May need octreotide if hypo recur (due to long ½ life of glibenclamide)
c. Octreotide + Somatostatin
i. Inhibits many endocrine systems
ii. Will cause ↓ insulin prodn
d. Needs admis
2. Factors that may have contributed to the onset of hypogly
a. Long acting sulphonylurea
b. Renal impairment with accumulation of active metabolites
3. Changes to her meds
a. Ø Glibenclamide
b. ?try gliclizide (shorter acting) 2.5 mg
c. Insulin may be most appropriate
d. Metformin C/I in renally impaired pts due to risk of lactic acidosis
e. ?Ø no tx

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