1. Diabetes Complications
DG van Zyl

2. The Ticking Clock

3. Different Diabetes Complications
Macro vascular
Micro vascular
Neuropathy
Infections

4. Mechanisms Genetic susceptibility *Repeated acute changes
in cellular metabolism
Hyperglycemia
Tissue damage
* Sorbitol accumulation
 NADH/NAD ratio
 Myoinositol
early glycation
** Forming advanced glycation end products
Independent accelerating factors:
- HT
- Hyperlipidemia
- Smoking
**Cumulative long term
changes in stable
macromolecules
Independent accelerating factors

5. Mechanisms of Hyperglycaemia Induced Damage
Increased Polyol - sorbitol Pathway flux
Increased AGES formation
Activation of protein kinase C
Increased Hexosamine pathway flux

6. Formation of AGEP

7. Macro vascular Complications

8. Macro-vascular Complications
Ischemic heart disease
Cerebrovascular disease
Peripheral vascular disease
Diabetic patients have a 2 to 6 times higher risk for
development of these complications than the
general population

9. Macro-vascular Complications
The major cardiovascular risk factors in the non-diabetic population (smoking, hypertension and hyperlipidemia) also operate in diabetes, but the risks are enhanced in the presence of diabetes.
Overall life expectancy in diabetic patients is 7 to 10 years shorter than non-diabetic people.

10. Macro-vascular Disease
Once clinical macro-vascular disease develops in diabetic patients they have a poorer prognosis for survival than normoglycemic patients with macrovascular disease
The protective effect females have for the development of vascular disease are lost in diabetic females

11. CAD Morbidity and Mortality in Type 2 DM
Framingham Data: 20 year follow-up:Age 45-74:
2-3 fold increase in clinically evident atherosclerotic disease in diabetics
women diabetics=male diabetics in terms of CAD mortality
Multiple Risk Factor Intervention Trial (MRFIT)
5000 men with type 2 DM
Followed for 12 years
Men with type 2 DM had absolute risk of CAD-related death 3 times higher than non-diabetic cohort
To further focus on the epidemiology of coronary disease in type 2 diabetes, it is important to understand that diabetics have a significantly increased risk when compared to their non-diabetic cohorts. Framingham data with 20 year follow-up on patients aged 45 to 74 revealed that diabetics had a 2-3 fold increase in clinically evident atherosclerotic disease. Furthermore, women diabetics were equal to male diabetics in terms of CAD mortality. There was a loss of the normal female cardiovascular protective benefit seen in non-diabetics when controlling for age and other CV risk factors. Similarly in the Multiple Risk Factor Intervention Trial which followed 5000 men with type 2 DM for 12 years, it was noted that men with type 2 DM had an absolute risk of CAD-related death which was 3 times higher than their non-diabetic cohort.

12. Risk Factor Clustering in Diabetes
Type 2 Diabetes at Diagnosis:
50% have hypertension
30% have dyslipidemia
UKPDS:
Prospective study
Newly detected type 2 DM:
335 with CAD, 8 year follow-up
Associated with elevated LDL-C, low levels of HDL-C, systolic hypertension
This slide illustrates the phenomenon of risk factor clustering in diabetic patients. In terms of patients with type 2 diabetes at diagnosis, 50% have hypertension and 30% have dyslipidemia in addition to their diabetes. In the United Kingdom prospective diabetes study (UKPDS), a prospective study looking at newly detected diabetic patients. Of the patients with newly detected diabetes 335 developed CAD over an 8 year follow-up. Of those patients 30% had high LDL-C, low HDL-c while 50% had systolic hypertension.

13. Cardiovascular Death Rates: MRFIT data
This slide shows that the age-adjusted CVD mortality rates per 10,000 person years increases steeply with increasing number of risk factors in patients with type 2 diabetes at baseline when compared to their non-diabetic cohorts. Note that at every level of risk factor, diabetics have a higher age-adjusted mortality rate. Also, there is a synergistic effect of diabetes and other risk factors such that the steep of the increase in risk is much greater in the diabetic population.
Stamler J., et al Diabetes Care: 16:

14. Risk of MI in Diabetes Haffner, SM et al NEJM: 339: 229-234
This data here shows the marked increase in the risk of myocardial infarction in type 2 diabetes. This data is from a Finnish study which compared the incidence of first MI in Non-diabetics to those with type 2 diabetes. Important points from this data include the fact that in diabetics with no history of MI have a similar incidence of MI when compared to patients who are non-diabetic and have had an MI. Note also that diabetics who have had an MI, have more than a 2 fold increase in risk of another MI compared to non-diabetics with a history of MI over 7 years of follow-up. Also, diabetics with MI have an approximately 9 fold increase in risk than patients without diabetes and have not had an MI.
This data supports current recommendations to treat diabetic patients as though they have established CAD when considering risk factor reduction.
Haffner, SM et al NEJM: 339:

15. Plasma Glucose as Independent Risk Factor
This study, published in diabetes care in 1995, revealed that when blood glucose is stratified by quintiles, fasting blood glucose is independently related to all cause, cardiovascular, and ischemic heart disease mortality. There was no clear threshold for this outcome-the lower the glucose, the better the outcome.
Andersson, DK et al. Diabetes Care 18:

16. Glycemic Control to Reduce CAD
DCCT trial:
1441 patients, type 1 diabetes
Randomized to intensive glycemic control vs. conventional therapy
Monitored prospectively for 6.5 years
Results:
Less retinopathy by 50%
Macrovascular complications: 41% reduction (not statistically significant)
-small number of events in young patient cohort
UKPDS:
3867 patients with newly diagnosed type 2 DM
Intensive vs. Conventional therapy
10 year follow-up
Microvascular endpoints improved
Trend only towards reduced incidence of MI ( p=0.052)
Intensive Glycemic control has been shown to be beneficial in terms of microvascular complications of diabetes such as retinopathy. There is much less convincing data regarding macrovascular complications. For example, in the Diabetes Control and Complications trial, 1441 patients with a mean age of 27 years and no significant retinopathy at baseline were randomized to intensive glycemic control: using insulin pump or 3 or more daily insulin injections targetting a glucose between 4 and 7. Patients were monitored for 6.5 years. Results showed a 50% reduction in retinopathy in the group with tight glycemic control. Macrovascular complications(cardiovascular and peripheral vascular) were reduced by 41% but this was not statistically significant. There were only a small number of events in a young patient cohort.
In the UKPDS, which randomized 3867 patients with newly diagnosed type 2 DM to intensive vs. conventional therapy. Over 10 years of follow-up, there was a trend only towards reduced incidence of MI which did not reach statistical significance.

17. Effect of Hypertension
The combination of hypertension and diabetes is a serious situation, posing increased predisposition to cardiovascular morbidity and mortality.
There is no doubt that hypertension occurs more commonly in diabetic patients, and confer a greater prospect of development of complications, it should therefore be taken as seriously as glycemic control when planning treatment strategies

18. Why worry about Hypertension in Diabetic patients
Treating hypertension can reduce the risk of:
Death 32%
Microvascular disease 37%
Stroke 44%
Heart failure 56%
UKPDS BMJ 1998;317:

19. Hypertension in Type 1 and 2 Diabetes
Develop after several years of DM
Ultimately affects ~30% of patients
Type 2
Mostly present at diagnosis
Affects at least 60% of patients

20. Pathophysiology of hypertension
Type 1 DM
Secondary to
nephropathy
Activation of the
RAAS
Type 2 DM
Hyperinsulinemia
Secondary to insulin resistance
Activation of the sympathetic nervous system

21. Goals of Treatment of Hypertension
Lower target for diabetic patients than non-diabetic patients:
130/85 vs. 140/90
UKPDS 38. BMJ 1998;317:
HOT. Lancet 1998;351:

22. Effect of Cholesterol
Hyperlipidemia can occur as result of poorly controlled diabetes, or may occur as a independent risk factor for macrovascular disease. About 25% of patients attending a diabetes clinic will have elevated lipid levels

23. Dyslipidaemia in DM
Most common abnormality is  s HDL and  s Triglyserides
A low HDL is the most constant predictor of CV disease in DM
Target lipid values: LDL <2.6 mmol/l, HDL >1.15 mmol/l, TG < 2.5 mmol/l

24. Micro vascular Complications

25. Eye Complications Cataracts
Non enzymatic glycation of lens protein and subsequent cross linking
Sorbitol accumulation could also lead to osmotic swelling of the lens but evidence of involvement in cataract formation is less strong

26. Eye Complications Retinopathy (stages) Background Pre-proliferative
Advanced diabetic eye disease
Maculopathy
Glaucoma

27. Diabetic Retinopathy (DR)
DR is the leading cause of blindness in the working population of the Western world
The prevalence increase with the duration of the disease (few within 5 years, 80 – 100% will have some form of DR after 20 years)
Maculopathy is most common in type 2 patients and can cause severe visual loss

28. Background Retinopathy
Micro aneurisms
Scattered exudates
Hemorrhages(flame shaped, Dot and Blot)
Cotton wool spots (<5)
Venous dilatations
Background retinopathy

29. Background retinopathy

30. Pre-Proliferative Retinopathy
Rapid increase in amount of micro aneurisms
Multiple hemorrhages
Cotton wool spots (>5)
Venous beading, looping and duplication
Proliferative retinopathy

31. Proliferative Retinopathy
New vessels (on disc, elsewhere)
Fibrous proliferation (on disc, elsewhere)
Hemorrhages (preretinal, vitreous)
Panretinal photo-coagulation

32. Proliferative retinopathy

33. Vitreous Bleeding

34. Rubeosis Iridis

35. Advanced Diabetic Eye Disease
Retinal detachment with or without retinal tears
Rubeosis iridis
Neovascular glaucoma

36. Maculopathy Macular edema (focal or diffuse) Ischaemic maculopathy
Focal and diffuse maculopathy are caused y microvascular leakage, leading to fluid and hard exudates in the area of the macula.
Ischaemic maculopathy is associated with areas of capillary non-perfusion and is difficult to detect. Hard exudates often occur in rings (circinate exudates) around the leaking area.

37. Maculopathy

38. Diabetic Nephropathy (DN)
Diabetes has become the most common cause of end stage renal failure in the US and Europe
About 20 – 30% of patients with diabetes develop evidence of nephropathy
The prevalence of DN is higher in Black Americans than in Whites (Figures for South Africa is not available)

39. Stages of Diabetic Nephropathy
Stage 3: Overt diabetic nephropathy
After 15 – 25 years in 35% of diabetic patients
Pronounced abnormalities of the glomeruli
GFR decline by 10 ml/min/year
Progressive clinical proteinuria
BP increase by 5 mmHg per year
Nor reversible but progression can be slowed by good glucose control and use of ACE inhibitor
Stage 4: ESRD
Final outcome after years
Glomerular closure
GFR < 10 ml/min
Invariably hypertensive
Irreversible

40. Stages of DN Stage I  glomerular filtration and kidney hypertrophy
Stage II
u-albumin excretion < 30mg/24h
Stage III
Microalbuminuria (30 – 300 mg/24h)
Stage I: This stage is usually not clinically evident
Stage II: Renal lesions are found on biopsy
Stage III: Without intervention the average increase in albuminuria in patients with type 1 DM is 20% per year. Blood pressure usually starts to increase once fixed albuminuria exist
Stages I – III are reversible

41. Stages of DN (cont) Stage IV
Overt nephropathy (> 300mg/24h, positive u dipstick)
Stage V
ESRD characterized by  blood urea and creatinine levels, hyperkalaemia and fluid overload
Stage IV: Kidney damage is considered to be irreversible at this stage and renal function deteriorates on average at a rate of 1mL per month. Without treatment uremia and death occur in 7 – 10 years. Because of late diagnosis of type 2 DM up to 15% of newly diagnosed diabetic patients are already in this stage.

42. Diabetic Neuropathy Sensorimotor neuropathy (acute/chronic)
Autonomic neuropathy
Mononeuropathy
Spontaneous
Entrapment
External pressure palsies
Proximal motor neuropathy

43. Sensorimotor Neuropathy
Patients may be asymptomatic / complain of numbness, paresthesias, allodynia or pain
Feet are mostly affected, hands are seldom affected
In Diabetic patients sensory neuropathy usually predominates

44. Complications of Sensorimotor neuropathy
Ulceration (painless)
Neuropathic edema
Charcot arthropathy
Callosities

45. Autonomic Neuropathy Symptomatic Postural hypotension Gastroparesis
Diabetic diarrhea
Neuropathic bladder
Erectile dysfunction
Neuropathic edema
Charcot arthropathy
Gustatatory sweating
Subclinical abnormalities
Abnormal pupillary reflexes
Esophageal dysfunction
Abnormal cardiovascular reflexes
Blunted counter-regulatory responses to hypoglycemia
Increased peripheral blood flow

46. Mononeuropathies Cranial nerve palsies (most common are n. IV,VI,VII)
Truncal neuropathy (rare)

47. Entrapment Neuropathies
Carpal tunnel syndrome (median nerve)
Ulnar compression syndrome
Meralgia paresthetica (lat cut nerve to the thigh)
Lat Popliteal nerve compression (drop foot)
All the above are more common in diabetic patients

48. Proximal Motor Neuropathy
Amyotrophy – most common proximal neuropathy, affects the Quadriceps muscles with weakness and atrophy
(synonym: Diabetic Femoral radiculo-neuropathy)

49. Diabetic Amyotrophy
Diabetic amyotrophy. This syndrome is known by several names, including diabetic proximal motor neuropathy and diabetic polyradiculoneuropathy. Patients typically present with pain and weakness in the proximal large muscles of the legs and pelvic area. Muscle wasting may be unilateral or bilateral, but is usually asymmetric with bilateral involvement.4 Patients complain of severe pain in the lumbar and sacral regions. Many patients report a loss of appetite and depression as well. Improvement may take from 6 months to 2 years. Immunotherapy may be beneficial and accelerate recovery.11

50. Thoracoabdominal Radiculopathy
Thoracoabdominal radiculopathy. Truncal radiculopathies are rare but can present at the initial diagnosis of diabetes.2 Nerve roots T8 through T12 are commonly affected. Patients complain of a tight bandlike or constricting pain in the chest or abdomen. The chest or abdominal wall skin becomes sensitive to the touch.2 Motor involvement may lead to abdominal muscle weakness, which may lead to herniation and an asymmetric bulge in the abdominal wall.3 Examination of spinal fluid may show an increase of protein.4 Prognosis is generally good; most patients recover within several months.

51. Sudomotor Dysautonomia
Patients often complain of hyperhidrosis or anhidrosis of the extremities, venous congestion, pain and redness of the feet, and gustatory sweating.5 Gustatory sweating is common in patients with cervical sympathetic denervation, demonstrated by profuse sweating of the face, neck, and upper trunk while eating.12

52. Summary
Diabetic neuropathy is a common complication, and result in significant morbidity
Diabetic neuropathy present in numerous ways
Hyperglycemia is the cause of diabetic neuropathy

53. Summary (cont) Diabetic neuropathy have bad consequences
Diabetic neuropathy can be prevented in only one way
Once diabetic neuropathy is present it can only be managed symptomatically
Early diagnosis and aggressive management can prevent progression

54. Infections
The association between diabetes and increased susceptibility to infection in general is not supported by strong evidence
However, many specific infections are more common in diabetic patients and some occur almost exclusively in them
Other infections occur with increased severity and are associated with an increased risk of complications

55. Infections (cont)
Several aspects of immunity are altered in patients with diabetes
There is evidence that improving glycemic control patients improves immune function
PMN leukocyte function is depressed, particularly when acidosis is also present. Leukocyte adherence, chemotaxis, and phagocytosis may be affected. Antioxidant systems involved in bactericidal activity may also be impaired.

56. Specific Infections Community acquired pneumonia
Acute bacterial cystitis
Acute pyelonephritis
Emphysematous pyelonephritis
Perinephric abscess
Fungal cystitis
Necrotizing fasciitis
Invasive otitis externa
Rhinocerebral mucormycosis
Emphysematous cholecystitis
CAP: Pneumococcal infection carries a higher risk of death in diabetic than non diabetic patients; S pneumoniae, S aureus, H influenzae
Acute bacterial cystitis: Bacteriuria more common in diabetic women; E coli, Proteus
Emphysematous pyelonephritis: emergency nephrectomy often required; E coli, gr- bacilli
Perinephric abscess: surgical drainage usually required; E coli, Gr- bacilli
Necrotizing fasciitis: High mortality; emergency surgery required; Gr- bacilli, anaerobes, Group A streptococci
Mucormycosis: Strong association with DKA; emergency surgery required
Invasive otitis externa: Prompt ENT consultation required; Pseudomonas aeruginosa
Emphysematous cholecystitis: High mortality; gallstones in 50%; emergency cholecystectomy required; Gr- bacilli, anaerobes

57. Rhino-Cerebral Mucormycosis

58. Screening and Management Strategy for Diabetes Complications

59. Screening for Macrovascular Complications
1. Examine pulses and for cardiovascular disease
2. Lipogram
3. ECG
4. Blood pressure
1-3 annually
4 every visit (quarterly)

60. Screening for Eye disease
Annually
Visual acuity (corrected with pinhole or lenses)
Careful eye examination (noting the clarity of the lens and any retinal changes (Ophthalmoscopy through dilated pupils)

61. Screening for Eye disease
When to refer?
Severe non-proliferative/proliferative retinopathy
Macular edema or exudates in close proximity to the macula
Cataract
Unexplained reduction in visual acuity

62. Screening for Nephropathy
Annually
Do one of the following:
u Albumin:Creatinine ratio (spot sample)
24h u Albumin excretion rate
Early morning Albumin concentration
(spot sample)
Dipstick for Microalbuminuria
If positive the test must be repeated twice in the ensuing 3 months. Microalbuminuria with incipient nephropathy is diagnosed if 2 or more of the tests are within the microalbumin range

63. Microalbuminuria Increased risk for overt nephropathy
Increased cardiovascular mortality
Increased risk of Retinopathy
Increased all-cause mortality
Thus
Microalbuminuria is an indication for screening for possible vascular disease and aggressive intervention to reduce all cardiovascular risk factors
Microalbuminuria indicates an increased risk for progression to overt nephropathy. Patients with microalbuminuria are between 9 and 20 more likely to progress to ESRD.
All-cause mortality increase 148% and CV mortality increase 15-fold.
In a 11-year follow up study, nearly 70% of diabetes patients with microalbuminuria developed retinopathy as opposed to none of the patients without microalbuminuria.

64. Screening Tests for Microalbuminuria
Category
24h u collection
(mg/24h)
Timed collection
(mg/min)
Spot collection
(mg/mg creat)
Normal
 30
 20
Microalbuminuria
Albuminuria Overt
 300
 200
Screening for microalbuminuria can be performed by three methods: 1) measurement of the albumin-to-creatinine ratio in a random spot collection; 2) 24-h collection with creatinine, allowing the simultaneous measurement of creatinine clearance; and 3) timed (e.g., 4-h or overnight) collection. The first method is often found to be the easiest to carry out in an office setting and generally provides accurate information; first-void or other morning collections are preferred because of the known diurnal variation in albumin excretion, but if this timing cannot be used, uniformity of timing for different collections in the same individual should be employed. Specific assays are needed to detect microalbuminuria because standard hospital laboratory assays for urinary protein are not sufficiently sensitive to measure such levels. Microalbuminuria is said to be present if urinary albumin excretion is >30 mg/24 h (equivalent to 20 µg/min on a timed specimen or 30 mg/g creatinine on a random sample).
False Positive Tests: Short-term hyperglycaemia, exercise, urinary tract infections, marked hypertension, heart failure, and acute febrile illness can cause transient elevations in urinary albumin excretion. If assays for microalbuminuria are not readily available, screening with reagent tablets or dipsticks for microalbumin may be carried out, since they show acceptable sensitivity (95%) and specificity (93%) when carried out by trained personnel. Because reagent strips only indicate concentration and do not correct for creatinine as the spot urine albumin-to-creatinine ratio does, they are subject to possible errors from alterations in urine concentration. All positive tests by reagent strips or tablets should be confirmed by more specific methods. There is also marked day-to-day variability in albumin excretion, so at least two of three collections done in a 3–6 month period should show elevated levels before designating a patient as having microalbuminuria.

65. Who to Screen For Microalbuminuria
Type 1 Diabetes
Begin with puberty
After 5 years duration of disease
Should be done annually there after
Type 2 Diabetes
Start screening at the Diagnosis of diabetes
Should be done annually there after
SCREENING FOR ALBUMINURIA — A routine urinalysis should be performed at diagnosis in patients with type 2 diabetes. If the urinalysis is positive for protein, a quantitative measure is frequently helpful in the development of a treatment plan. If the urinalysis is negative for protein, a test for the presence of microalbumin is necessary. Microalbuminuria rarely occurs with short duration of type 1 diabetes or before puberty; therefore, screening in individuals with type 1 diabetes should begin with puberty and after 5 years' disease duration. Because of the difficulty in precise dating of the onset of type 2 diabetes, such screening should begin at the time of diagnosis. After the initial screening and in the absence of previously demonstrated microalbuminuria, a test for the presence of microalbumin should be performed annually

66. Management of Nephropathy
Improvement of glycemic control
Treatment of hypertension
Treatment with angiotensin converting enzyme inhibitors
Restriction of dietary intake of protein
Once persistent elevation in u-Albumin is
found refer to a Internist or Nephrologist
Tight glucose control prevents the development of and ameliorates established diabetic nephropathy
Lowering blood pressure slows the progression of decline in renal function and improves patient survival
ACE inhibitors preserve renal structure and function independent of their effect on systemic blood pressure
High dietary protein intake accelerates the deterioration of renal function

67. Screening for Neuropathy
128 Hz tuning fork for testing of vibration perception
10g Semmers monofilament
The main reason is to
identify patients at risk
for development of
diabetic foot

68. Using of the Monofilament
A standardized filament is pressed against part of the foot. When the filament bends, its tip is exerting a pressure of 10 grams (therefore this monofilament is often referred to as the 10gram monofilament). If the patient cannot feel the monofilament at certain specified sites on the foot, he/she has lost enough sensation to be at risk of developing a neuropathic ulcer. The monofilament has the advantage of being cheaper than a biothesiometer, but to get results which can be compared to others, the monofilament needs to be calibrated to make sure it is exerting a force of 10 grams

69. Management of Neuropathy
Burning pain – TADs / Capsaicin
Lancinating pain – Anticonvulsants / TAD / Capsaicin
Painful cramps – Quinidine sulphate
Restless legs - Clonazepam
Other causes should be excluded especially: alcohol, vit B12 deficiency and uremia
UKPDS, DCCT – good glycemic control can largely prevent neuropathy

70. Do’s and Don'ts of foot care
Patient should
check feet daily
Wash feet daily
Keep toenails short
Protect feet
Always wear shoes
Look inside shoes before putting them on
Always wear socks
Break in new shoes gradually

71. Conclusion
This is just an outline of the major diabetic complications, and doesn't aim to be comprehensive
All complications are preventable with good glycaemic control
The progression of most complications can be halted if detected early and appropriate therapy instituted