Types of Diabetes

1
Types of Diabetes

• General disorders (usually complex inheritance)
• Insulin-dependent DM (IDDM - type 1) ABSOLUTE
  DEFICIENCY
• Non-Insulin-dependent DM (NIDDM - type 2) INS
  RESISTANCE ? ? CELL DYSFUNCTION
• Gestational DM (type 4)
• Specific single gene disorders (very rare)
• Insulin gene mutations
• Maturity-Onset DM of Youth (e.g. Glucokinase
  gene mutations, MODY2)
• Insulin receptor gene mutations (e.g.
  Leprechaunism)
• Other specific causes
• Pancreatic disease or surgery
• DM associated with endocrinopathies (e.g.
  Cushings)
• DM associated as part of genetic syndromes (e.g.
  Prader-Willi)

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Incidence of Diabetes (/100,000)
43 Finland 17 UK 1 Japan
IDDM
Ethnic variation (USA)
5000 Pimas 540 African 440 White
NIDDM
800 S Europe 100 N Europe
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Drug Therapy I - Insulin
Human peptide sequence Pig and beef insulin
differ by 1 (AlaB30Thr) and 2 (ThrA8Ala,
ileA10Val) amino acids respectively.

• Typical production by non-diabetic adult is
  0.2-0.5 U/kg/day
• Approx 5050 split between basal and prandial (in
  response to meals)
• Short plasma t1/2 of 5-6 mins
• 50 cleared through liver so portal venous gt
  systemic

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Problems with subcutaneous Insulin

• Absorption variable and dependent on
• Short-acting
• Formulation Intermediate-acting (complexed with
  protamine)
• Long-acting (crystal suspensions with Zn)
• Site Abdomengtbuttockgtant. thighgtdorsal arm
• Depth intramuscular gt subcutaneous
• Absorption from these sites gives unphysiological
  INS profiles
• Compared to IV administration
• Gives systemic levels gt portal vein.
• Slow in onset (30-120m for peak levels)
• Slow in offset (up to 6h) - risk post-prandial
  hypo

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Common Insulin Regimens
BD regimen using fixed mixture of soluble and
intermediate-acting INS
BD or OD long-acting INS with short-acting
soluble with each meal.
Profile in C provided using a continuous SC pump
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Drug therapy II Sulphonylureas

• - 1st generation e.g. chlorpropamide, tolbutamide
  LARGELY OBSOLETE
• - 2nd generation e.g. glibenclamide, gliclazide
• Actions
• Acutely release INS by depolarising ?-islet
  cells (block iKATP)
• Effect not sustained chronically
• ? Significant extapancreatic effects e.g.
  upregulation of INS receptors
• 2nd generation v potent (100xgt1st)
• Effective o.d. despite short t1/2 (lt5h)
• Side effects
• Hypoglycaemia (may be prolonged if long t1/2)
• Hyponatraemia (potentiate ADH action)
• Flushing (disulfiram-like)
• Chlorpropamide worst offender

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Drug therapy III antihyperglycaemics

• BIGUANIDES (metformin)
• No effect on insulin release do not cause
  hypoglycaemia even in over dose
• Appears to have post-receptor effect on INS
  action
• Typically used in combination with a
  sulphonylurea
• Lactic acidosis a rare problem (lt1 in 10,000
  patient-years)
• Avoid if significant hepatic/renal impairment
• THIAZOLIDINEDIONES (-glitazones)
• Effective in various insulin-resistant states
• Do not cause hypoglycaemia
• Fall in INS and lipid levels 2ary to fall in BG?
• Does not affect INS function in normal tissues
• Act as ligands for PPARG (Peroxisome-Proliferator
  -Activated Receptor Gamma)
• PPARs are members of nuclear hormone receptor
  superfamily
• Form heterodimers with retinoid X to regulate
  gene transcription

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Treatment Goals

• The goal is to correct the metabolic
  complications of insulin deficiency
• ACUTE hyperglycaemia (causing polyuria/thirst)
• ketoacidosis
• macro vascular atherosclerotic e.g.
  stroke/AMI
• CHRONIC
• micro vascular nephropathy
• retinopathy
• neuropathy
• NB Progression of CHRONIC complications are
  directly related
• to the degree of hyperglycaemia - long-term
  efficacy of tight glycaemic
• control demonstrated by UKPDS (type 2) and DCCT
  (type 1) trials.

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Major Therapeutic Trials 1

• DCCT (Diabetes Control Complications Trial)
  1983-1993
• 1441 Type 1 patients (726 no retinopathy or
  microalbuminuria 715 non-prolif retinopathy and
  microalbuminuria)
• Randomised to INTENSE or CONVENTIONAL Rx
• Average follow-up 6.5 years
• INTENSE Rx reduced by approx 60 the risk of
  retinopathy, nephropathy and neuropathy.
• 3-fold increase in risk of severe hypo in INTENSE
  group.
• INTENSE tds INS or pump frequently adjusted
  by at least qds BG
• CONVENTIONAL od/bd INS and single daily BG or
  urine check

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Major Therapeutic Trials 2

• UKPDS (UK Prospective Diabetes Study) 1977-1997
• 5102 newly diagnosed Type 2 patients from 23
  centres
• Median follow up of 11 years
• Randomised to diet or Rx (INS, SU or MF)
• All Rx showed similar efficacy over diet
• Good glycaemic reduced risk of microvasculopathy
• Approx 35 reduction for each 1 fall in HbA1c
• Macrovascular disease risk not affected
• ? function deteriorated steadily during the study
  regardless of Rx
• Only reduced by anti-hypertensive Rx in a sub
  study where the impact of aggressive BP control
  mirrored HOT trial.

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Control Targets in Diabetes

• Tight glycaemic control should be the goal
  whenever possible
• e.g. ADA targets HbA1c lt7 and fasting BG
  4.4-6.7 mmol/l
• Are there risks of tight glycaemic control ?
• elderly AMI, stroke, syncope
• YES (hypoglycaemia)
• young (lt7) impaired brain development ?
• What about other cardiovascular risk factors ?
• Cardiovascular risk factors act synergistically ?
• Tight control of BP (lt140/85) and cholesterol (TC
  lt5)
• Stop smoking
• Aspirin for high-risk patients?

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BP control in Diabetics BHS guidelines

• Type I
• prevalence of HT similar to non-DM until
  nephropathy develops (microalbuminuria or
  proteinuria)
• ACE-inhibitors 1st-line antihypertensives reduce
  rate of decline renal function and progression
  microalbuminuria ? proteinuria
• Target BP lt140/80 (lt125/75 if proteinuria
  present)
• ACE-I useful in normotensives?
• Type 2
• High prevalence (gt70 have BP gt140/90)
• No antihypertensive class favoured gt2 agents
  often needed to reach target of 140/80

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Newer drug developments

• True monomer INS
• Lispro (LysB28-ProB29)
• Aspart (AspB28)
• Very long-acting BASAL INS
• HOE 901 (GlyA21, di-arginyl B30)
• New INS Delivery Routes ?
• Nasal
• Oral
• Rapid-acting Insulin secretogogues e.g. non-SU
  Repaglitine
• (only close KATP channels in the presence of
  glucose)
• Modifiers of Post-Prandial Hyperglycaemia (PPHG)
• Agents to delay gastric emptying amylin
  derivatives

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Further Information
American Diabetic Association (ADA) web site
http//www.diabetes.org/ Diabetes branch of
NIDDK http//www.niddk.nih.gov/ BHS guidelines
http//www.hyp.ac.uk/bhs PPT Slide show
at http//www-clinpharm.medschl.cam.ac.uk