1. Complications of Diabetes Mellitus [Chronic]
Hasan Aydin, MD Department of Endocrinology and Metabolism Yeditepe University Medical Faculty

2. Complications of Diabetes Mellitus
Chronic complications
Microvascular
retinopathy
Nephropathy
neuropathy
Macrovascular
cerbrovascular, cardiovascular, peripheral vascular disease
Acute complications
diabetic ketoacidosis
diabetic nonketotic, hyperosmolar coma
hypoglycemia

3. Introduction
Adults with diabetes have an annual mortality of 5.4% (double the rate for non-diabetic adults)
Life expectancy is decreased on average by 5-10 years
Although the increased death rate is mainly due to cardiovascular disease, deaths from non-cardiovascular causes are also increased.
A diagnosis of diabetes immediately increases the risk of developing various clinical complications that are largely irreversible and due to microvascular or macrovascular disease.

4. DM Complications Major Determining Factors Duration Glycemic Control
Type 1 vs. Type 2

5. Type 2 Diabetes is a Progressive Disease Macrovascular Changes
Diagnosis
350
300
250
200
150
100 50
Postprandial
Glucose
Glucose
(mg/dl)
Fasting
Glucose
250
200
150
100 50
Insulin Rasistance
function (%)
Relative beta-cell
Insulin
Level
Beta-cell Deficiency
Obesity IGT Diabetes
Uncontrolled
Hyperglycemia
Prevention
OAD
Insulin
Clinical
Signs
Macrovascular Changes
Microvascular Changes
Years
D Kendall, R Bergenstal, International Diabetes Center

6. Type 2 DM Starts Years Before Diagnosis
At the diagnosis of Type 2 DM
% of pts have retinopathy Harris MI et al . Diab Care, 21: 1992.
Hamman RF et al. Diabetes, 38: 1989
5 – 10% proteinuria
Haffner SM et al. Diab Care, 12: 1989

7. Prevention is more rewarding than Management of Complications

8. Microvascular Complications

9. Microvascular Complications
Microvascular complications are specific to diabetes and do not occur without longstanding hyperglycaemia
Both T1DM and T2DM are susceptible to microvascular complications
The duration of diabetes and the quality of diabetic control are important determinants of microvascular disease

10. Microvascular Complications
A continuous relation exists between glycaemic control and the incidence and progression of microvascular complications.
HTN and smoking also have an adverse effect on microvascular outcomes.

11. “Tight Glycemic Control” reduces microvascular and macrovascular complications

12. Glycemic Control and Complications

13. Mortality due to Diabetes40
Risk -
reduction 32% P
=0.019 30
convetional
tight control
Mortality (%) 20 10 1 2 3 4 5 6 7 8 9
yıl
UK Prospective Study Group.

14. Possible molecular mechanisms of diabetes-related complications.
Harrison's Principles of Internal Medicine, 16th Edn

15. Consequences of hyperglycemia-induced activation of protein kinase C (PKC)
Vascular Health and Risk Management 2007:3(6):

16. Mechanisms of AGE Action

17. Pathophysiology of Microvascular Disease
Structural changes
thickening of the capillary basement membrane
Functional changes
increased capillary permeability
increased blood flow and viscosity
disturbed platelet function
Chemical changes in basement membrane composition
increased type IV collagen and its glycosylation products

18. Diabetic Retinopathy

19. Retinopathy Diabetic retinopathy is a progressive disorder
It is the commonest cause of blindness in age
Damage to the retina arises from a combination of microvascular leakage and microvascular occlusion
A fifth of p’ts with newly discovered type 2 diabetes have retinopathy at the time of diagnosis.

20. Retinopathy
In type 1 diabetes, vision threatening retinopathy almost never occurs in the first five years after diagnosis or before puberty.
After 15 years, however, almost all type 1 diabetes and two thirds of type 2 diabetes have background retinopathy
Vision threatening retinopathy is usually due to neovascularisation in type 1 diabetes and maculopathy in type 2 diabetes.

21. Retinopathy
Depending on the relative contribution of leakage or capillary occlusion, maculopathy is divided into three types:
exudative maculopathy (when hard exudates appear in the region of the macula),
ischaemic maculopathy (characterised by a predominance of capillary occlusion which results in clusters of haemorrhages)
edematous maculopathy (extensive leakage gives rise to macular edema).

22. Classification of Diabetic Retinopathy
Neovascularization (4 categories)
– Nonproliferative (NPDR)
1. Early to moderate NPDR
2. Severe NPDR (preproliferative)
– Proliferative (PDR)
1. Non-high-risk PDR
2. High-risk PDR

23. Non-Proliferative Diabetic Retinopathy

24. Severe NPDR (Pre-Proliferative)

25. Proliferative Diabetic Retinopathy

26. Retinal Neovascularization
NVE
vitreous
hemorrhage

27. BDR with Clinically Significant Macular Edema (CSME)

28. Treatment of Diabetic Retinopathy (Systemic)
Control
Blood sugar
Blood pressure
Cholesterol
Treat
Heart failure
Kidney failure
Avoid smoking

29. Treatment of Diabetic Retinopathy (Ocular)
Laser
Focal for macular edema
Pan-retinal for neovascularization
Vitrectomy
Medications

30. Laser Treatment for Diabetic Macular Edema

31. Vitrectomy Surgery

32. Diabetic Nephropathy

33. Diabetic Nephropathy
Over 40% of new cases of end-stage renal disease (ESRD) are attributed to diabetes.

34. Nephropathy
Diabetic nephropathy is characterised by proteinuria >300 mg/24 h, increased BP, and a progressive decline in renal function.
In the early stages, overt disease is preceded by a phase known as incipient nephropathy (or microalbuminuria), in which the urine contains trace quantities of protein (not detectable by traditional dipstick testing).
Microalbuminuria is defined as an albumin excretion rate of mg/24 h and is highly predictive of overt diabetic nephropathy

35. Treatment of Diabetic Nephropathy
Hypertension Control
Goal: lower blood pressure to <140/90 mmHg
Antihypertensive agents
Angiotensin-converting enzyme (ACE) inhibitors
captopril, enalapril, lisinopril, benazepril, fosinopril, ramipril, quinapril, perindopril, trandolapril, moexipril
Angiotensin receptor blocker (ARB) therapy
candesartan cilexetil, irbesartan, losartan potassium, telmisartan, valsartan, esprosartan
Calcium channel blockers

36. Treatment of Diabetic Nephropathy
Glycemic Control
Preprandial blood glucose mg/dl
A1C <6.5%
Postprandial blood glucose <140 mg/dl
Self-monitoring of blood glucose (SMBG)
Medical Nutrition Therapy
Restrict dietary protein to RDA of 0.8 g/kg body weight per day

37. Treatment of End-Stage Renal Disease
There are three primary treatment options for individuals who experience ESRD:
1. Hemodialysis
2. Peritoneal Dialysis
3. Kidney Transplantation

38. Diabetic Neuropathy

39. Diabetic Neuropathy
About 60-70% of people with diabetes have mild to severe forms of nervous system damage, including:
Impaired sensation or pain in the feet or hands
Slowed digestion of food in the stomach
Carpal tunnel syndrome
Other nerve problems
More than 60% of nontraumatic lower-limb amputations in the United States occur among people with diabetes.

40. Diabetic Neuropathy Damage to nerve fibres and capillaries
Symptoms depend on nerves involved
Motor fibres → Muscular weakness
Sensory fibres → Loss of sensation
also prickling, tingling, aching and pain
Autonomic fibres → loss of function
functions not under conscious control such as digestion, bladder, genitals, cardiovascular.

41. Diabetic Neuropathy Other Consequences Risk factors
Diabetic foot (15% of all diabetics)
Compression neuropathies
eg carpal tunnel syndrome
Risk factors
Smoking, >40 years old, poor glucose control
Affects Type 1 and Type 2

42. Classification of Diabetic Neuropathy
Symmetric polyneuropathy
Autonomic neuropathy
Polyradiculopathy
Mononeuropathy

43. Symmetric Polyneuropathy
Most common form of diabetic neuropathy
Affects distal lower extremities and hands (“stocking-glove” sensory loss)
Symptoms/Signs
Pain
Paresthesia/dysesthesia
Loss of vibratory sensation

44. Complications of Polyneuropathy
Ulcers
Charcot arthropathy
Dislocation and stress fractures
Amputation

45. Treatment of Symmetric Polyneuropathy
Glucose control
Pain control
Alphalipoic acid
Anticonvulsants (gabapentin, pregabalin)
Tricyclic antidepressants
Topical creams
Foot care

46. Autonomic neuropathy
Affects the autonomic nerves controlling internal organs
Peripheral
Genitourinary
Gastrointestinal
Cardiovascular
Is classified as clinical or subclinical based on the presence or absence of symptoms

47. Peripheral Autonomic Dysfunction
Contributes to the following symptoms/signs:
Neuropathic arthropathy (Charcot foot)
Aching, pulsation, tightness, cramping, dry skin, pruritus, edema, sweating abnormalities
Weakening of the bones in the foot leading to fractures
Peripheral autonomic denervation can contribute to many different symptoms including changes in the texture of the skin, itching, edema, and sweating abnormalities in the feet. Peripheral autonomic dysfunction can also contribute to neuropathic arthropathy and fractures. Patients who already suffer from symmetric polyneuropathy are at greater risk for Charcot arthropathy. Patients should be aware of symptoms such as swelling, redness, heat, strong pulse, and insensitivity of the foot.
Peripheral autonomic dysfunction can be diagnosed using specialized techniques such as microelectrode recordings of postglanglionic C fibers. It can also be diagnosed using galvanic skin responses and quantitative sudomotor axon reflex testing (QSART) to measure the presence of sympathetic innervation in hands and feet Vascular responses can also be measured to determine peripheral sympathetic denervation. Constriction of the blood vessels in the presence of heat indicates vascular denervation

48. Peripheral Autonomic Dysfunction
Treatment
Foot care/elevate feet when sitting
Eliminate aggravating drugs (tranquilizers, antidepressants, diuretics)
Reduce edema
midodrine
diuretics
Support stockings
Screen for CVD

49. Genitourinary Autonomic Neuropathy

50. Gastrointestinal Autonomic Neuropathy
Symptoms/Signs
Gastroparesis resulting in anorexia, nausea, vomiting, and early satiety
Diabetic enteropathy resulting in diarrhea and constipation
Treatment
Other causes of gastroparesis or enteropathy should first be ruled out
Gastroparesis - Small, frequent meals, metoclopramide, erythromycin
Enteropathy - loperamide, antibiotics, stool softeners or dietary fiber

51. Cardiovascular Autonomic Neuropathy
Symptoms/Signs
Exercise intolerance
Postural hypotension
Treatment
Discontinue aggravating drugs
Change posture (make postural changes slowly, elevate bed)
Increase plasma volume

52. Polyradiculopathy Lumbar polyradiculopathy (diabetic amyotrophy)
Thigh pain followed by muscle weakness and atrophy
Thoracic polyradiculopathy
Severe pain on one or both sides of the abdomen, possibly in a band-like pattern
Diabetic neuropathic cachexia
Polyradiculopathy + peripheral neuropathy
Associated with weight loss and depression

53. Mononeuropathy Peripheral mononeuropathy
Single nerve damage due to compression or ischemia
Occurs in wrist (carpal tunnel syndrome), elbow, or foot (unilateral foot drop)
Symptoms/Signs
numbness
edema
pain
prickling

54. Mononeuropathy Cranial mononeuropathy Mononeuropathy multiplex
Affects the 12 pairs of nerves that are connected with the brain and control sight, eye movement, hearing, and taste
Symptoms/Signs
unilateral pain near the affected eye
paralysis of the eye muscle
double vision
Mononeuropathy multiplex

55. MACROVASCULAR COMPLICATIONS

56. Macrovascular Complications
Angina.
Myocardial infarction.
Transient ischaemic attacks.
Cerebrovascular accident.
Claudication lower limb.
Neuropathy / infection.

57. Macrovascular Complications
Atherosclerotic disease accounts for most of the excess mortality in diabetes.
In the UKPDS, fatal cardiovascular events were 70 times more common than deaths from microvascular complications.
The relation between glucose concentrations and macrovascular events is less powerful than for microvascular disease;
Smoking, BP, proteinuria, and cholesterol concentration are more important risk factors for atheromatous large vessel disease in diabetes.

58. Macrovascular Complications
Hyperlipidaemia is no more common in well controlled type 1 diabetes than it is in the general population.
In type 2 diabetes, total and LDL concentrations are also similar to those found in non-diabetic people, but type 2 diabetes is associated with a more atherogenic lipid profile, in particular low HDL and high small, dense, LDL particles.

59. Macrovascular Complications
HTN affects at least half of diabetes.
In UKPDS, tight BP control (mean 144/82 mm Hg) achieved significant reductions in the risk of stroke (44%), heart failure (56%), and diabetes related deaths (32%), as well as reductions in microvascular complications (for example, 34% reduction in progression of retinopathy). One third of p’ts required three or more antihypertensive drugs to maintain a target BP <150/85 mm Hg.
In another recent study (hypertension optimal treatment study) rates of CV events in type 2 diabetes were reduced even further when combination treatment was used to aim for target diastolic BP <80 mm Hg.

60. Unmodifiable Risk Factors
Age >50
Gender
Hereditary
Risks are classified as unmodifiable (things you can’t change) and modifiable (things you can change).
Unmodifiable risk factors include:
Gender: males are at a much greater risk of premature CVD. Women are protected until menopause.
Hereditary: the risk associated is partly due to genetic inheritance of increased cholesterol, hypertension and increased susceptibility towards obesity and diabetes.

61. Modifiable Risk Factors
Smoking
Inactivity
Nutrition
Obesity (BMI > 30)
Excessive smoking & alcohol intake

62. Medical Risk Factors Hypertension (BP>130/80mmHg) High cholesterol
Poor glycemic control (HbA1c>7%)
Microalbuminuria

63. Coronary Heart Disease
The incidence and severity of coronary heart disease events are higher in diabetes, and several clinical features are worth noting.
The diabetes subgroups in the major secondary prevention studies of cholesterol reduction (Scandinavian simvastatin survival study (4S) and cholesterol and recurrent events (CARE) trial) show a beneficial effect of statins.

64. Peripheral Vascular Disease
Atheromatous disease in the legs, as in the heart, tends to affect more distal vessels—for example, the tibial arteries—producing multiple, diffuse lesions that are less straightforward to bypass or dilate by angioplasty.
Medial calcification of vessels ( Mönckeberg's sclerosis ) is common

65. Stroke
85% of acute strokes are atherothrombotic, and the rest are haemorrhagic (10% primary ICH , 5% SAH ).
The risk of atherothrombotic stroke is two to three times higher in diabetes, but the rates of haemorrhagic stroke and TIA are similar to those of the non-diabetic population.
Diabetes are more prone to irreversible rather than reversible ischaemic brain damage, small lacunar infarcts are common.

66. Stroke
Stroke p’ts with diabetes have a higher death rate and a poorer neurological outcome with more severe disability.
Maintaining good glycaemic control immediately after a stroke is likely to improve outcome, but the long term survival is reduced because of a high rate of recurrence.
Antihypertensive treatment is effective in preventing stroke.

67. Erectile Dysfunction
A common complication of diabetes, occurring in up to half of men aged over 50 years (compared with 15-20% in age matched non-diabetic men), although the exact prevalance is unknown because of likely underreporting.
Pathogenesis is multifactorial, with autonomic neuropathy, vascular insufficiency, and psychological factors contributing to the clinical picture. The condition causes appreciable social and psychological problems for many p’ts, and its importance should not be underestimated.
Sildenafil, Tadalafil, which is reported to have a 50-70% success rate in diabetes, is an important advance.

68. DIABETIC FOOT SYNDROME

69. Foot Problems and Diabetes
Neuropathy
Peripheral: loss of protective sensation
Autonomic: loss of ability to sweat
Motor: loss of structure/muscle tone
Peripheral Vascular Disease
Impaired circulation in legs and feet
Increased incidence of inflammation and infection
High risk of ulcers, gangrene and amputations when person also has neuropathy

70. Illustration of ulcer due to repetitive stress
Callus formation
Subcutaneous hemorrhage
Breakdown of skin
Deep foot infection with osteomyelitis

71. Diabetic Foot Ulcers

72. Diabetic foot ulcers

73. Diabetic Foot Ulcers

74. Diabetic foot ulcers

75. Prevention Foot exam by a health professional at every medical visit
Comprehensive exam annually
Vascular
Musculoskeletal
Skin and soft tissue
Education

76. T h a n k Y o u !