A very difficult case of diabetes

1
A very difficult case of diabetes

• Dr Vincent Connolly

2
8 Years Old

• 2y bumping into objects
• 3y retinal pigmentation optic atrophy combined
  retinal receptor dystrophy
• gt 97th centile for weight
• 3rd centile for height
• Normal intellect
• 4y progressive hearing difficulty sensori-motor
  hearing loss
• 6y bilateral hearing aids
• Investigation of short stature/obesity/small
  genitalia
• ITT max GH 3mu/l

• Height 120cm, weight 37.8 kg
• BMI 26.25 kg/m2
• Pituitary tests normal
• GTT normal
• Triglycerides raised
• GH low
• Linear growth, advanced bone age
• Raised AST
• Visual acuity L 1/60 R 1/60

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Insulin Resistance

• 9y totally blind
• 13y investigations
• Fasting insulin 85mu/l
• Stimulated insulin gt 700mu/l
• Profoundly insulin resistant

• 14y delayed secondary sexual characteristics
• Hypogonadal / micro penis / Hypoplastic scrotum
• Small testes / pubic hair normal
• Elevated gonadotrophins, testosterone 8 nmol/l

4
Polydipsia, polyuria

• Diabetes mellitus RBG 18mmol/l
• Weight 71.8 kg BMI 32.8
• Diet alone
• Oral agents
• Modest weight reduction
• Hba1c normal range, HBGM 5-11

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What type of diabetes is this?

• Type 1
• Type 2
• Secondary
• MODY
• Diabetes associated with another diagnosis

6
Relevant Genetic Syndromes Associated With
Diabetes

• Diabetes-deafness syndrome mtDNA
• Maternally transmitted NIDDM deafness
• MELAS mtDNA
• (N)IDDM, myopathy, encephalopathy, lactic
  acidosis, stroke-like episodes
• Alstroms -
• NIDDM, retinopathy, deafness, obesity. GH def
• LMB 11, 16, 4
• IGT, retinopathy, mental retardation, obesity,
  polydactyly

7
Relevant Genetic Syndromes Associated With
Diabetes

• Leprechaunism 19
• NIDDM, IUGR, dysmorphic features
• Rabson-Mendenhall 19
• (N)IDDM, acanthosis nigricans, pineal hyperplasia
• Kearns-Sayre mtDNA
• NIDDM, ophthalmoplegia, retinal deg,
  cardiomyopathy
• Larsens -
• Cone dystrophy, endocrine dysfunction, abnormal
  LFTs, obesity, NIDDM, hypogonadism

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Teenage Years

• Genetics Mitochondrial DNA - NAD
• LFTs AST 131, GGT 417
• Lipids cholesterol 7.2 mmol/l Triglycerides
  6.1mmol/l
• Diabetes hba1c 10.9
• Hyperinsulinaemic isoglycaemic clamp
• Ave insulin conc 115mu/l
• M value 48mg/m2/min (obese diabetics 80)

9

• Hypogonadism
• LH 40.4iu/l, FSH 53.0 IU/l
• Testosterone 7.4nmol/l
• Bones
• Hip, BMD reduced gt2sdmean
• Intellect
• University, European studies
• Family history
• Mothers name fathers name
• Maternal great aunt blind aged 14

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24y Current Situation

• Blind- combined receptor defect
• Deaf- bilateral sensori-neural
• Diabetes- insulin resistance
• Obesity- BMI 32.8kg/m2
• Primary Hypogonadism
• Abnormal liver function
• Growth hormone deficiency

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What is the optimal diabetes treatment plan ?

• Metformin alone
• Acarbose
• Metformin Sulphonylurea
• Insulin /- Metformin
• Thiazoledinedione

12
Diabetes Management

• Stepwise increase in standard therapy
• Hba1c 11
• Insulin metformin combination
• Hba1c 8.9
• Introduction of Rosiglitazone, phasing out of
  insulin
• Hba1c 7

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Change in HbA1c
Metformin
Insulin Metformin
Rosiglitazone Metformin
Metformin
Insulin Metformin
Rosiglitazone Metformin
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Change in BMI
Rosiglitazone Metformin
Insulin Metformin
Metformin
Rosiglitazone Metformin
Insulin Metformin
Metformin
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Mode of action of Thiazolidinediones
Insulin resistance
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Mode of action of Thiazolidinediones

• Thiazolidinediones act as insulin sensitisers by
  promoting the uptake of triglycerides into
  adipocytes.
• The net effect is to decrease the systemic
  availability of fatty acids.
• Insulin résistance improves as fatty acid uptake
  in muscle is also reduced.
• Thiazolidinediones lower triglycerides and
  increase HDL-cholesterol levels.
• Rosiglitazone is associated with an increase in
  LDL-cholesterol.

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Common Features of Alstroms

• nystagmus and photodysphoria in early infancy
• Progressive pigmentary retinopathy (cone-rod
  dystrophy) leading to blindness
• Childhood obesity, often moderating to
  high-normal weight in adulthood
• Mild to moderate bilateral sensorineural hearing
  loss
• Congestive heart failure secondary to dilated
  cardiomyopathy in infancy or early adulthood
• Normal extremities / absence of polydactyly or
  syndactyly

• hyperinsulinemia / insulin resistance
• Non-insulin dependent diabetes mellitus (type 2
  diabetes or NIDDM) developing in early adulthood
• Progressive chronic nephropathy that presents as
  tubular dysfunction
• Normal intelligence with some reports of delayed
  early developmental milestones

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Alstrom Syndrome International
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Balanced Translocation
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The Genetics

• The gene was mapped to the 2p13 breakpoint on
  the maternal allele to a genomic fragment of 1.7
  kb
• A novel gene, ALMS1
• The paternal copy of the gene, had a frameshift
  mutation
• 12.9-kb transcript of ALMS1 encodes a protein of
  4,169 amino acids

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ALMS 1 Gene Expression
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Problems

• Marked weight gain
• Fluid retention
• Reports of cardiomyopathy associated with
  Alstroms

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Should the glitazone be continued?

• Continue glitazone
• Stop glitazone

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Next step

• Novomix 30, 40 units bd
• BG gt 10mmol/l
• HbA1c gt10

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What future treatment plan would you recommend?

• Continue insulin
• Add metformin
• Add GLP1 analogue (exenatide)
• Add DPP-IV inhibitor (sitagliptin)
• Manage obesity
• Not sure

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Incretins

• Peptides secreted by the intestinal mucosa in
  response to food intake
• (GLP-1)
• Glucose-dependent insulinotrophic polypeptide
  (GIP)

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What does GLP mean ?

• Glucose lowering protein
• Glucagon like peptide
• Good looking presenter

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Incretins and glycaemic control7,8
Bloodglucose control
DPP-4enzyme rapidly degrades incretins
Adapted from 7. Drucker DJ. Cell Metab.
20063153165. 8. Miller S, St Onge EL. Ann
Pharmacother 2006401336-1343.
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Mode of action of sitagliptin8
Bloodglucose control
Sitagliptin is a DPP-4 inhibitor and inhibits the
breakdown of incretins and thereby increases
active incretin levels
DPP-4enzyme rapidly degrades incretins
DPP-4 dipeptidyl peptidase 4 inhibitor
Adapted from 8. Miller S, St Onge EL. Ann
Pharmacother 2006401336-1343.
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Physiological effects of incretins

• ? prandial insulin secretion
• ? glucagon secretion
• ? Acid secretion and GI motility (? gastric
  emptying
• ? satiety and ? food intake
• ? ß cell protection
• ? Cardiovascular effects

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What is this?

• Monitor lizard
• Gila lizard
• Damien Hirst creation

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Exenatide

• Synthetic equivalent of exendin-4
• Found in the saliva of the Gila monster
• 53 homology with human GLP-1
• Now available in US for treatment of T2D (Byetta,
  Lilly/Amylin)
• Given as bd sc injection
• Licensed as adjunct to MFN, SU or both
• Due for release in UK anytime now

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Summary of Exenatide data

• 2yr extension of RCTs (open label)
• Sustained effect on glycaemic control
• Further wt loss 2.7kg vs 4.7kg
• Add on to TZDs successful
• Exenatide LAR
• Benefit in islet cell transplants

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Comparison
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(No Transcript)
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Common Surgical Procedures for Weight Loss
DeMaria E. N Engl J Med 20073562176-2183
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Weight Maintenance after Bariatric Surgery
Sjöström L, Lindroos AK, Peltonen M et al. N
Engl J Med. 200435126
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Results

• Diabetes remission 73 (surgical) versus 13
  (medical), plt0.001
• Greater percentage of wt loss at two yrs and
  lower baseline A1c values were independently
  associated with remission
• Percentage of weight loss explained most of the
  variance
• 20 (surgical) versus 1.4 (medical), plt0.001

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Future treatment plan

• Continue insulin
• Add metformin
• Add GLP1 analogue (exenatide)
• Add DPP-IV inhibitor (sitagliptin)
• Manage obesity
• Not sure

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Trial of exenatide

• Awaiting results!!!

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Thank you