Cutaneous complications of Diabetes Vaginal yeast infections Onychomycosis (fungal infection of the nails)
Cutaneous complications of Diabetes Yellow Nails
Cutaneous complications of Diabetes Itching Often a result of yeast infection, dry skin, and/or poor circulation
Cutaneous complications of Diabetes Digital Sclerosis Tight, thick, waxy skin most commonly on the back of the hand Finger joints can become stiff
Cutaneous complications of Diabetes Acanthosis Nigricans Hyperpigmented plaques. Most commonly found in armpits, neck, and groin
Cutaneous complications of Diabetes Diabetic Dermopathy. Light brown, scaly, atrophic patches Usually occur on the shins.round or oval, reddish-brown, scaly papules and plaques, ranging in size from 0.5 cm.Lesions do not itch, hurt, or open up.
Diabetic Dermopathy Diabetic Dermopathy
Diabetic Dermopathy Diabetic Dermopathy
Cutaneous complications of Diabetes Necrobiosis Lipoidica Diabeticorum Similar to diabetic dermopathy but spots are fewer in number and larger and deeper Can be itchy, painful, and difficult to treat
Cutaneous complications of Diabetes (Granuloma Annulare)
Cutaneous complications of Diabetes Pigmented Purpura Brown to red macules and patches often coexists with diabetic dermopathy.
Cutaneous complications of Diabetes Diabetic blisters Bullosis Diabeticorum Most commonly on the backs of fingers, hands, toes, feet, and sometimes on legs or forearms Look like burn blisters
Cutaneous complications of Diabetes Eruptive Xanthomatosis Firm, yellow, pea-like enlargements in the skin Most often on backs of hands, feet, arms, legs, and buttocks.
Cutaneous complications of Diabetes Diabetic Foot Ulcers
Cutaneous complications of Diabetes Peripheral Vascular Disease Diabetics are more prone to develop atherosclerosis, which can result in peripheral vascular disease Claudication Delayed healing Cold, pale, hairless legs and feet Thick nails Ulcers
Cutaneous complications of Diabetes Gangrene
Necrobiosis Lipoidica Diabeticorum One of the best known cutaneous markers for diabetes Initially presents with well-circumscribed erythematous papules, which develop into large, irregularly delineated plaques with a waxy, yellow center
Necrobiosis Lipoidica Diabeticorum The epidermis becomes thin and transparent, allowing underlying vasculature to become visible The involved peripheral tissue is slightly raised and has a reddish-blue color About 85% of NLD cases occur on the legs bilaterally Lesions can also appear on the face, scalp, hands, forearms, or abdomen
Necrobiosis Lipoidica Diabeticorum(cont.)
Necrobiosis Lipoidica Diabeticorum(cont.)
Bullosis Diabeticorum Rare a distinct marker for diabetes usually on the feet and toes, but occasionally on the hands and fingers Bullae are blisters spontaneously appearing from normal skin. They are usually 0.5 to several centimeters in size, and contain a clear, sterile, viscous fluid
Bullosis Diabeticorum (cont.) Two major types of bullae, intraepidermal and subepidermal, have been defined Intraepidermal bullae are clear, sterile, nonhemorrhagic blisters that generally heal on their own within two to five weeks without scarring or atrophy. Most patients developing this type of bullae are men between ages 40 and 75 with long-standing diabetes, peripheral neuropathy, and good circulation to the involved extremity
Bullosis Diabeticorum (cont.) Subepidermal bullae are the least common of the two types of bullosis diabeticorum. These blisters are similar to the intraepidermal blisters except they occasionally are hemorrhagic and may heal with scarring and atrophy
Bullosis Diabeticorum (cont.)
Granuloma Annulare Granuloma annulare is identified by its characteristic annular or arciform plaques that begin as flesh-colored, red, or reddish-brown papules symmetrically spread across the upper trunk, neck, arms, and occasionally the legs
Acanthosis Nigricans Rough, velvety, dark patches of skin on the back of the neck It is now evident that a close association exists between AN, obesity, and insulin resistance
GIT COMPLICATIONS OF DIABETES Gastroparesis Delayed gastric emptying Intestinal enteropathy (which can cause diarrhea, constipation, and fecal incontinence) Nonalcoholic fatty liver disease.
GIT COMPLICATIONS OF DIABETES Patients with gastroparesis may present with early satiety, nausea, vomiting, bloating, postprandial fullness, or upper abdominal pain.
GIT COMPLICATIONS OF DIABETES Esophageal manifestations of diabetic neuropathy, including abnormal peristalsis, spontaneous contractions, and impaired lower esophageal sphincter tone, result in heartburn and dysphagia
GIT COMPLICATIONS OF DIABETES The delayed gastric emptying in patients with gastroparesis is thought to be caused primarily by impaired vagal control. Other contributing factors include the impairment of inhibitory nitric oxide-containing nerves, damage to the interstitial cells of Cajal, and underlying smooth muscle dysfunction
GIT COMPLICATIONS OF DIABETES Abnormal internal and external anal sphincter function caused by neuropathy can lead to fecal incontinence. Nonalcoholic fatty liver disease is generally diagnosed because of persistent elevation in hepatic transaminase levels. Diabetes is more common in patients with hepatitis C infection than in the general population.
GIT COMPLICATIONS OF DIABETES Causes of cirrhosis linked to diabetes include nonalcoholic fatty liver disease, hemochromatosis, and hepatitis C infection. OHD can cause hepatotoxicity. The entire GI tract can be affected, including the mouth, esophagus, stomach, small intestine, colon, liver, and pancreas, leading to a variable symptom complex.
Epidemiology of DR RISK of developing DR: Type I or IDDM – 70% Type II or NIDDM - 39%
RISK FACTORS: Duration of diabetes Poor control of Diabetes Pregnancy Hypertension Nephropathy Obesity and hyperlipidemia Smoking
Microangiopathy which has features of both microvascular leakage and occlusion
Larger vessels may also be involved
Loss of pericytes results in distention of weak capillary wall producing microaneurysmswhich leak
Blood-retinal barrier breaks down causing plasma constituents to leak into the retina –retinal oedema, hard exudates
Vascular Endothelial Growth Factor (VEGF) is produced by hypoxic retina
VEGF stimulates the growth of shunt and new vessels
Classification of DR I. Non-proliferative DR (NPDR) Mild Moderate Severe Proliferative DR (PDR) III. Clinically significant macular oedema (CSME) - May exist by itself or along with NPDRand PDR
Mild NPDR At least one microaneurysm - earliest clinically detectable lesion
Hard or soft exudates
Moderate NPDR Microaneurysms and/or dot and blot hemorrhages in at least 1 quadrant Soft exudates (Cotton wool spots) Venous beading or IRMA (intraretinal microvascular abnormalities)
Mild and Moderate Non- proliferative DR was previously known as Background DR
Severe NPDR Any one of the following 3 features is present Microaneurysms and intraretinal hemorrhages in all 4 quadrants Venous beading in 2 or more quadrants Moderate IRMA in at least 1 quadrant Known as the 4-2-1 rule
Severe Non-proliferative DR was known as the Pre-proliferative DR
Clinically significant Macular Oedema Retinal oedema close to fovea Hard exudates close to fovea Presents with dimness of vision By itself or along with NPDR or PDR
CSME – Hard exudates close to fovea and associated retinal thickening
Proliferative DR (PDR) Characterized by Proliferation of new vessels from retinal veins New vessels on the optic disc New vessels elsewhere on the retina
Neovascular Glaucoma Complication of rubeosis iridis New vessels cause angle closure Mechanical obstruction to aqueous outflow Intra ocular pressure rises Pupil gets distorted as iris gets pulled Eye becomes painful and red Loss of vision
PREVENTION OF COMPLICATIONS By early institution of appropriate treatment This requires early detection of DR in its asymptomatic treatable condition By routine fundus examination of all Diabetics (cost effective screening) And appropriate referral to ophthalmologist
Mild and Moderate NPDR
- No specific treatment for retinopathy
Good metabolic control to delay progression
Control of associated Hypertension, Anemia and Renal failure
Severe and very severe NPDR
Close follow up by Ophthalmologist
Clinically significant macular oedema
Laser photocoagulation to minimise risk of visual loss
Retinal laser photocoagulation as per the judgment of ophthalmologist (in high risk eyes)
It converts hypoxic retina (which produces ANGIOGENIC factors) into anoxic retina
Screening protocol for Diabetic retinopathy Screening once in a 1 year Diabetics with normal fundus Mild NPDR Screening once in 6 months Moderate NPDR
Referral to Ophthalmologist Visual Symptoms Diminished visual acuity Seeing floaters Painful eye Fundus findings - Macular oedema/hard exudates close to fovea - Proliferative DR - Vitreous hemorrhage - Moderate to severe and very severe NPDR
Cataract obscuring fundus view
Referral to Ophthalmologist Presence of Risk Factors - Pregnancy - Nephropathy
Simulation of defective vision as experienced by a Diabetic whose vision has been affected by Diabetic retinopathy Normal Defective
DIRECT OPHTHALMOSCOPY Examination of the fundus of the eye To screen for Diabetic Retinopathy After dilatation of both eyes with 0.5% tropicamide Flashlight test, prior to dilatation to detect eyes with shallow AC Procedure will be demonstrated
View of the retina through an ophthalmoscope
Normal fundus views of Right and left eye
Mild NPDR – Microaneurysms, Dot and Blot hemorrhages
Moderate NPDR with CSME
Circinate retinopathy – Hard exudates in a ring around leaking aneurysms
Moderate – Severe NPDRCotton wool patches Hemorrhages - 4 quadrants
Moderate – Severe NPDRCotton wool patches Hemorrhages - 4 quadrants
Severe NPDR Cotton-wool patches, venous segmentation
Very severe NPDR
Venous beading, - scars of laser spots,
CSME in different stages of NPDR
CSME in different stages of NPDR
Proliferative DR – New vessels elsewhere on the retina along the superior-temporal vessels
PDR – New vessels on disc
PDR –New vessels on disc and New vessels elsewhere on retina
UROGENITAL COMPLICATIONS OF DIABETES Erectile dysfunction (ED) is a condition that affects a man's ability to get and sustain an erection that leads to positive sexual experiences. Although most men do encounter trouble having an erection from time to time, the problem is not generally thought to be ED unless the symptoms are consistent for 3 months or more.
UROGENITAL COMPLICATIONS OF DIABETES Women may have problems with sexual response and vaginal lubrication. Urinary tract infections and bladder problems occur more often in people with diabetes. Damage to these autonomic nerves can hinder normal function. Reduced blood flow resulting from damage to blood vessels can also contribute to sexual dysfunction.
UROGENITAL COMPLICATIONS OF DIABETES Retrograde Ejaculation Retrograde ejaculation is a condition in which part or all of a man’s semen goes into the bladder instead of out the tip of the penis during ejaculation. Retrograde ejaculation occurs when internal muscles, called sphincters, do not function normally. A sphincter automatically opens or closes a passage in the body.
UROGENITAL COMPLICATIONS OF DIABETES With retrograde ejaculation, semen enters the bladder, mixes with urine, and leaves the body during urination without harming the bladder. A man experiencing retrograde ejaculation may notice that little semen is discharged during ejaculation or may become aware of the condition if fertility problems arise. Analysis of a urine sample after ejaculation will reveal the presence of semen.
UROGENITAL COMPLICATIONS OF DIABETES Sexual problems may include Decreased vaginal lubrication, resulting in vaginal dryness Uncomfortable or painful sexual intercourse Decreased or no desire for sexual activity Decreased or absent sexual response
UROGENITAL COMPLICATIONS OF DIABETES Decreased or absent sexual response can include the inability to become or remain aroused, reduced or no sensation in the genital area, and the constant or occasional inability to reach orgasm.
UROGENITAL COMPLICATIONS OF DIABETES Common bladder problems in men and women with diabetes include the following: Overactive bladder. Damaged nerves may send signals to the bladder at the wrong time, causing its muscles to squeeze without warning. The symptoms of overactive bladder include urinary frequency—urination eight or more times a day or two or more times a night
UROGENITAL COMPLICATIONS OF DIABETES urinary urgency—the sudden, strong need to urinate immediately urge incontinence—leakage of urine that follows a sudden, strong urge to urinate.
UROGENITAL COMPLICATIONS OF DIABETES Poor control of sphincter muscles. Sphincter muscles surround the urethra—the tube that carries urine from the bladder to the outside of the body—and keep it closed to hold urine in the bladder. If the nerves to the sphincter muscles are damaged, the muscles may become loose and allow leakage or stay tight when a person is trying to release urine.
UROGENITAL COMPLICATIONS OF DIABETES Urine retention may also lead to overflow incontinence—leakage of urine when the bladder is full and does not empty properly. Symptoms of urinary tract infections can include a frequent urge to urinate pain or burning in the bladder or urethra during urination cloudy or reddish urine in women, pressure above the pubic bone in men, a feeling of fullness in the rectum
UROGENITAL COMPLICATIONS OF DIABETES sexual and urologic problems appear to be more common in people who have poor blood glucose control have high levels of blood cholesterol have high blood pressure are overweight are older than 40 Smoke are physically inactive
MUSCULOSKETAL COMPLICATIONS IN DIABETES
Diabetic Muscle Infarction Rare Painful muscle swelling, usually in thigh Mass expands over days to weeks
Neuropathic Arthropathy(Charcot Joint) First described in 1868 by Jean Martin Charcot in patients with tabes dorsalis Destructive arthropathy in diseases which impair sensory function, but maintain normal motor function
Charcot Joint Most common in MTPs, tarso-metatarsals, tarsus, ankle and interphalangeal joints Single, painless, swollen, deformed joint in setting of peripheral neuropathy Periarticular soft tissues loosen thereby causing joint laxity and subluxation Repetitive microtrauma with weight bearing damages the joint
Hand Abnormalities Carpal Tunnel Syndrome Dupuytren’s contracture Flexor tenosynovitis Limited joint mobility Each condition present in ~ 20% patients with diabetes
Dupuytren’s Contracture Fibrosis in and around the palmar fascia with nodule formation Contraction of the palmar fascia causes flexion contractures of digits The 3rd and 4th finger most commonly effected in patients with diabetes, compared to the 5th finger in patients without diabetes Present in 15-40% of patients with diabetes Prevalence increases with age
Adhesive capsulitis ( frozen shoulder) Progressive painful restriction of shoulder movement Joint capsule adheres to humeral head 3 phases: painful, adhesive, resolution 10-30% in diabetics, 2-10% in controls 17% patients with adhesive capsulitis have diabetes Associated with age and duration of diabetes
Limited Joint mobility Diagnosis “prayer sign” “table top test” To differentiate from Dupuytren’s: Limited joint mobility usually involves 4 fingers Absence of taut fibrotic bands
Diabetic Sclerodactyly Thickening and waxiness of skin Usually on dorsa of fingers Associated with limited joint mobility Similar to skin changes of scleroderma (absent antibodies, Raynaud’s, calcinosis, ulceration, tapering)
Diabetic neuropathy There are two types of diabetic neuropathy Diffuse peripheral neuropathy primarily affects the limbs, damaging the nerves of the feet and hands. Focal—or localized neuropathy affects specific nerves, most commonly in the torso, leg, or head.
Autonomic neuropathy Autonomic neuropathy is the other form of diffuse neuropathy and it affects the heart and other internal organs.
Autonomic neuropathy Diabetic neuropathy can lead to muscular weakness, Loss of feeling or sensation, and loss of autonomic functions such as Digestion, Erection, Bladder control, and sweating
Autonomic neuropathy Impaired urination and sexual function Bladder infections Stomach disorders, due to the impaired ability of the stomach to empty (gastric stasis) Nausea, Vomiting and bloating Dizziness,
Autonomic neuropathy Lightheadedness, and fainting spells Loss of appetite Abdominal swelling, Heat intolerance, Impotence, Diarrhea,
Autonomic neuropathy Constipation, Dizziness with standing, Difficulty urinating and urinary incontinence. Tachycardia, Exercise intolerance, Orthostatic hypotension, Gastroparesis, Erectile dysfunction,
Autonomic neuropathy Sudomotor dysfunction, Impaired neurovascular function, “brittle diabetes,” and hypoglycemic autonomic failure. Esophageal enteropathy, gastropathy, and fecal incontinence)
Focal neuropathy Common symptoms of focal neuropathy include: Pain in the front of a thigh Severe pain in the lower back Pain in the chest or stomach Ache behind an eye Double vision Itching Paralysis on one side of the face
Diabetic neuropathy In severe diabetic neuropathy loss of sensation can lead to injuries that are unnoticed, progressing to infections, ulceration and possibly amputation.
Diabetic neuropathy The exam may include: a screening test for lost sensation nerve conduction studies to check the flow of electric current through a nerve electromyography (EMG) to see how well muscles respond to electrical impulses transmitted by nearby nerves.
Diabetic neuropathy ultrasound to show how the bladder and other parts of the urinary tract are functioning sometimes a nerve biopsy may be performed.
Diabetic peripheral neuropathy Sensory Motor (myelin) Characteristic features of Peripheral Neuropathy are Bilateral, symmetrical Progressive Paraesthesias, pain, muscle atrophy Glove and stocking type usually affects distal parts of limbs then ascend upwards
Neuropathic ulcers FEATURES: Painless, surrounded by callus At pressure points. associated with good foot pulses May not be associated with gangrene
Nephropathy An angiopathy of glomeruli Is a micro vascular complication of diabetes marked by albuminuria and a deteriorating course from normal renal function to end stage renal failure. ESRD
Risk factors for nephropathy Hypertension Hyperglycemia Microalbuminuria Ethnicity Male gender Family history Cigarette smoking
Nephropathy The syndrome was discovered by British physician Clifford Wilson (1906–1997) and German-born American physician Paul Kimmelstiel (1900–1970) and was published for the first time in 1936.
Nephropathy Usually manifests 15–25 years after diagnosis of diabetes and affects 25-40% of patients under the age of 30 years. The disease is progressive and may cause death two or three years after the initial lesions, and is more frequent in men.
Nephropathy The glomeruli and kidneys are typically normal or increased in size initially, thus distinguishing diabetic nephropathy from most other forms of chronic renal insufficiency, wherein renal size is reduced (except renal amyloidosis and polycystic kidney disease).
Signs and Symptoms Approximately 25% to 40% of patients with DM 1 ultimately develop diabetic nephropathy (DN), which progresses through five predictable stages.
Stage 1 (very early diabetes) Increased demand upon the kidneys is indicated by an above-normal glomerular filtration rate (GFR). Hyperglycemia leads to increased kidney filtration This is due to osmotic load and to toxic effects of high sugar levels on kidney cells Increased Glomerular Filtration Rate (GFR) with enlarged kidneys All this results in nephromegaly
Stage 2 (developing diabetes) Clinically silent phase with continued hyper filtration and hypertrophy .The GFR remains elevated or has returned to normal, but glomerular damage has progressed and leads to next stage that is chracterised by microalbuminuria with excretion of albumin in the range of 30-300 mg/day . Normal persons excrete less than 30mg/day. at this stage the disease process is probably reversible.
Significant microalbuminuria will progress to end-stage renal disease (ESRD). Therefore, all diabetes patients should be screened for microalbuminuria on a routine basis. 162
Stage 3 (overt, or dipstick-positive diabetes) In this stage albumin is more than 300 mg in a 24 hour period. The urine becomes "dipstick positive,” Albumin more than 300 mg/24 hour is called macroalbuminuria (defined as >300 mg/day (200 microgram/min). from this stage the disease is irreversible and a steady decline in glomerular filtration occurs at a rate of 1 ml/minute per month. the stage of macroalbuminuria may progress to nephrotic syndrome. If proteins are more than 3gm/24 hours then it results in nephrotic syndrome.
Stage 3 (overt, or dipstick-positive diabetes) Hypertension (high blood pressure) typically develops during stage 3. Basement membrane thickening occurs due to deposition of AGEP
Stage 4 (late-stage diabetes) Glomerular damage continues, with increasing amounts of protein albumin in the urine. The kidneys’ filtering ability has begun to decline steadily, and blood urea nitrogen (BUN) and creatinine (Cr) has begun to increase.
Stage 4 (late-stage diabetes) With further progression the azotaemia develops and progression to renal failure and uraemia is inevitable. The glomerular filtration rate (GFR) decreases about 10% annually. Almost all patients have hypertension at stage 4.
Stage 5 (end-stage renal disease, ESRD) GFR has fallen to <10 ml/min and renal replacement therapy (i.e., haemodialysis, peritoneal dialysis, kidney transplantation) is needed.
Glomerular Histology: The glomerular capillary wall is composed of an endothelial cell layer (blood side), a thick basement membrane, and epithelial cell layer (urine side).
(i) Glomerular Endothelium Theglomerular endothelium is fenestrated. The fenestrae (0.07 to 0.1 mm-micrometers- in maximal diameter) allow the passage of electrolytes, proteins, and globulin. However, platelets (3 mm), red cells (7 mm) and neutrophils (15 mm) can't pass through the endothelial layer.
(ii)Glomerular Basement Membrane (GBM): The GBM is a tri-laminar structure, 0.3 microns in thickness, composed of collagen, proteoglycans and laminin. It is product of the fusion of the endothelial and epithelial basement laminae. The dense central GBM area, or lamina densa, is due to the overlapping of the two laminae. Around 50% of the GBM is collagen IV.
NORMAL GBM. LEFT - a single glomerulus. There are one million of these in each kidney. RIGHT - a close up of the GBM (G) around part of one tiny blood vessel in a glomerulus (red circle in left hand diagram)
The negative charge of the GBM has been attributed to the presence of the heparan sulphate proteoglycan (HSPG) called perlecan. These negatively charged molecules are geometrically arranged in clusters separated by about 0.003 µm from each other. This anionic molecular sieve restricts the passage of molecules according to size and charge. Water, salts, glucose, amino acids and neutral, or cationic, molecules with radii less that 0.0035 µm are filtered with relative ease. The albumin molecule measures 0.0035 µm and is negatively charged. Therefore its filtration is restricted.
Presence of protein in the urine is a sign that either the charge or the distance between the anionic clusters, or both, are pathologically altered. The presence of red cells in the glomerular urine, is certain indication of GBM ruptures. Other classical constituents of the basement membrane are type IV collagen, laminin, and entactin.
Mesangium Mesangium a cellular network membrane like and in the inner layer of basement membrane surrounding the glomerular capillaries that helps support the capillary loops.
The intra-capsular glomerular capillary network is kept together by the mesangiumthat is composed of mesangial cells type I and II, and other tissue matrix. Mesangial type I cells are monocytes with phagocytic functions. These cells can extend cytoplasmic projections into the glomerular capillary. They also "clean" the mesangium of materials that leak from the capillary lumen into the matrix. These cells are stimulated by cytokines to produce free radicals and cytotoxic peptides.
Mesangial type II cells are myofibroblasts with the ability to contract upon ADH and angiotensin stimulation. Their contraction causes a reduction of the effective glomerular filtration area. Mesangial Matrix is a tissue mesh composed of different types of collagens (I, III, IV), laminin and proteoglycans.
Three major histological changes occur in the glomeruli of persons with diabetic nephropathy. Mesangial expansion is directly induced by hyperglycemia, perhaps via increased matrix production or glycosylation of matrix proteins. the cells mesangical that surrounds to glomerular vessels increases as a result of depot similar material to basement membrane. GBM thickening occurs. Glomerular sclerosis is caused by intraglomerular hypertension (induced by renal vasodilatation or from ischemic injury induced by hyaline narrowing of the vessels supplying the glomeruli).
Glomerular Hyper filtration Glucose provides an osmotic diuretic effect Result is increased renal filtration, leading to glomerular hypertrophy Glomerular pressure increases Kidney responds with hypertrophy of epithelium and endothelium Accelerates glomerular cell failure Result is premature glomerulosclerosis
Metabolic Perturbations Oxidant Stress - related to glomerular hypertrophy and abnormal metabolism Non-enzymatic glycosylation of macromolecules - particularly basement membrane (BM) Activation of glucose metabolizing enzymes Cytokine and other humoral imbalances
Non enzymatic Glycosylation Biochemical studies have shown that basement membranes in diabetes include excess amounts of type IV collagen, the main component of basement membranes, and decreased amounts of proteoglycans Both changes decrease the permeability of capillaries and disturb leukocyte diapedesis, oxygen diffusion, nutrition and metabolic waste removal. Altered charge on BM may explain albuminuria Macrophage receptor activation leads to IL1, TNF production which stimulates matrix AGEP formation leads to abnormal collagen, increased toxic oxygen species
Humoral Imbalances in DM Nephropathy Insulin Deficiency Elevated Glucagon Concentrations Increased Transforming Growth Factor(TGF)-ß Increased angiotensin II Abnormally regulated thromboxanes and endothelins Abnormal insulin like growth factor (IGF)-1 Elevated platelet derived growth factor (PGDF)
Role of TGF-ß Stimulates extracellular matrix synthesis Inhibits extracellular matrix degradation Up regulates protease inhibitors; down regulates matrix degrading enzymes Stimulates synthesis of integrins (matrix receptors) Key role in glomerular and tubuloepithelial hypertrophy, basement membrane thickening, and mesangial matrix expansion TGF-ß has been implicated in a number of chronic, scaring diseases
Angiotensin II and Thrombospondin (TSP1) can both stimulate the production of transforming growth factor-β (TGF-β) by tubuloepithelial cells and fibroblasts. TGF-β, in turn, causes proliferation of fibroblasts and tubuloepithelial cells. TGF-β ultimately increases extracellular matrix proteins, likely by several mechanisms. TGF-β stimulates production of several growth factors including basis fibroblast growth factor (bFGF) and platelet derived growth factor (PDGF) that stimulate the formation of extracellular matrix (ECM) proteins.
Ultrastructural changes of the glomerular basement membrane in diabetic nephropathy revealed by newly devised tissue negative staining method.
The normal human GBM showed a fine meshwork structure consisting of fibrils forming the small pores.
The diameter of these pores was slightly smaller than that of human albumin molecules.
The GBM in patients with diabetic nephropathy showed irregular thickening.
At higher magnification, unknown cavities and tunnel structures, which were not seen in normal controls, were observed in the thickened GBM.
In some portions, these cavities presented a honeycomb-like appearance. The diameters of the cavities and tunnels were far larger than the dimensions of albumin molecules. These enlarged structures are believed to allow serum protein molecules to pass through the GBM from the capillary lumen to the urinary space. These results suggest that the cause of massive proteinuria in diabetic nephropathy is the disruption of the size barrier of the GBM.
Glomerular and vascular pathology is linked to hyperglycemia. Changes in glomerular basement membrane structure occur very early in diabetic nephropathy, before even microalbuminuria is apparent. Collagen IV deposition is directly stimulated by hyperglycaemia and increased urinary levels indicate changes in the glomerular basement membrane. Contributing factors include the formation of advanced glycosylation end products (AGEs) due to non-enzymatic glycosylation of capillary basement membranes, as a consequence of long-term hyperglycaemia.
Non-enzymatic glycosylation has recently attracted increasing interest as a crucial pathophysiologic event behind all these hyperglycaemia-related alterations and in the pathophysiology of the development of diabetic complications. Proteins and lipids exposed to aldose sugars go through reactions which are not enzyme-dependent, and generation of reversible Schiff bases or Amadori products take place. Later, through further molecular rearrangements, irreversible advanced glycosylation end products (AGEs) are formed. This process also takes place during normal ageing, but in diabetes their formation is accelerated to an extent related to the level and duration of hyperglycaemia.
Hence large studies have shown a delay in onset or slowing of the progression of these complications if near normo-glycaemia can be maintained. The glycated proteins cross-link, contributing to basement membrane (and mesangial) thickening, (culminating in the kidney in nodular glomerulosclerosis), as well as loss of the normal selective permeability (leading to proteinuria, retinal hard exudates and microhaemorrhages).
The potential pathophysiological significance of AGEs is associated with their accumulation in plasma, cells and tissues and their contribution to the formation of cross-links, generation of reactive oxygen intermediates and interactions with particular receptors on cellular surfaces AGEs have direct effects on the host response by affecting tissue structures, e.g. by increasing collagen cross-links, which is followed by changes in collagen solubility and turnover. Thickening of basement membranes is partly due to glycosylation of membrane proteins or entrapment of glycosylated serum proteins into basement membrane It is evident that AGEs can interact with cell functions, tissue remodelling and inflammatory reactions in several different ways.
When Ang II is increased, greater AT1 receptor-mediated constriction of efferent than afferent arterioles increases single nephron glomerular filtration rate and raises intraglomerular pressure, causing glomerular hypertension. Sustained or severe increases in intraglomerular pressure can lead to GBM damage, glomerular endothelial dysfunction, and ultimately, extravasation of protein into Bowman’s capsule. In addition to hypertension, conditions like diabetes that are associated with increased oxidative stress (increased formation of reactive oxygen species) independent of hypertension and glyco-oxidative modification of proteins (AGEs) comprising the glomerular basement membrane can lead to extravasation of protein.
Glomerular hypertension can lead to injury to the glomerular basement membrane causing it to leak plasma proteins into the urine. Attempts by the proximal tubules to reabsorb this filtered protein causes injury to the tubular cells, activates an inflammatory response, and is associated with the development of lipid metabolic abnormalities that create further oxidative stress on the already compromised glomerulus. The resultant tubular inflammatory response and renal microvascular injury activate pathways that lead to fibrosis and scarring of both glomerular and tubular elements of the nephron ultimately leading to contracted kidneys.
An additional consequence of glomerular hypertension and resultant reduction in glomerular filtration rate (GFR) activates growth factors and cytokines that promote an influx of monocytes and macrophages into the vessel wall and into the renal interstitium, and also causes the differentiation of renal cells into fibroblasts. Monocytes, macrophages and fibroblasts are capable of producing those growth factors and cytokines that activate pathways leading to expansion of extracellular matrix, fibrosis and loss of both tubular and glomerular structures.
Collagen IV is the principal component of the glomerular basement membrane and it is released into the urine during its turnover. Increased urinary levels of collagen IV are found in several conditions where glomerular injury is found, particularly in diabetic nephropathy. Collagen IV is too large to cross the glomerular membrane (MW 540 000) and so urinary collagen IV is a specific sensitive indicator of changes to the structure of extracellular matrix of the kidney. Unlike serum creatinine, that measures changes in glomerular function, increased levels of urinary collagen IV indicate that damage is occurring to the renal tissue. Urinary collagen IV is a very early and specific biomarker for pathological changes to the glomerular membrane, particularly in diabetic nephropathy.
Summary Pathological lesions in DM The Armani-Ebstein change (or Armani-Ebstein cells) consists of deposits of glycogen in the tubular epithelial cells (pars straight of proximal convoluted tubule and loop of Henle).
Summary Pathological lesions in DM Because most diabetics are treated before this stage, it is very rare to see it at the present time. It appears in decompensated diabetics with glycemia higher than 500 mg/dL and in the presence of severe glycosuria; it is a reversible alteration without functional manifestations.
Summary Pathological lesions in DM Diabetic neuropathy involves two distinct pathological patterns that may or may not coexist. In the diffuse form which is more common there is widening of the glomerular basement membrane together with generalised mesangial thickening .
Summary Pathological lesions in DM the basement of glomerular capillaries thicken and can obliterate the blood vessels. The glomerular sclerosis is diffuse, but in 50% of cases it is accompanied with nodular sclerosis. The nodular component denominated Kimmelstiel-Wilson nodules is pathognomic of diabetes.
Summary Pathological lesions in DM In the nodular form large accumulations of PAS positive material Glycosylation End-products are deposited at the periphery of glomerular tufts , the Kimmelsteil-wilson leision.
Summary Pathological lesions in DM In addition there may be hyalinization of afferent and efferent arterioles, drops in bowman's capsule, fibrin caps, and occlusion of glomeruli and interstitial fibrosis. Deposition of albumin and other proteins occurs in both glomeruli and tubules.
Summary Pathological lesions in DM In short Microangiopathy Atherosclerosis Diffuse glomerulosclerosis or nodular diabetic glomerulosclerosis (Kimmelstiel Wilson nodules) Tubulointerstitial fibrosis
Nodular Glomerulosclerosis – KW lesion.
Summary Pathological lesions in DM Arteriosclerosis and hyalinosis of afferent and efferent arterioles . Necrotizing renal papillitis. Infections &Pyelonephritis. Nephrotic syndrome End stage kidney
Summary Pathological lesions in DM A kidney biopsy confirms the diagnosis. However, your doctor can diagnose the condition without a biopsy if you meet the following three conditions: 1.Persistent protein in the urine 2.Diabetic retinopathy 3.No other kidney or renal tract disease A biopsy may be done, however, if there is any doubt in the diagnosis
Nephropathy Nephropathy leads to Nephrotic syndrome Pyelonephritis End stage renal failure
Treatment of nephropathy Factors that favor the regression of microalbuminuria include better blood sugar control, lower blood pressure, lower serum cholesterol and triglycerides, recent onset and lower levels of microalbuminuria, and less glomerular hyperfiltration.
Treatment of nephropathy Early screening Spot urine albumin : creatinine ratio 24 hour urine collection dipstick Tight glycemic control
Treatment of nephropathy ACE inhibitors if creatinine less than 3mg/dl Use ACEI as first line, if not tolerated, use ARB. Use the maximum dose as tolerated If still hypertensive or proteinuric, consider using combination ACEI and ARB, or ACEI and diuretics
Treatment of nephropathy ACE inhibitors or ARB have a strong antiproteinuric effect apart from their antihypertensive actions Increasing the dose of the ACEI or ARB beyond the optimum antihypertensive doses further reduces proteinuria Antiproteinuric effect is enhanced by a low Na diet or diuretic
Treatment of nephropathy 0.8g/kg/day proteins Antilipids Thiazide diruritics Vit E
Treatment of nephropathy Keep BP slightly less than 130/85 mmHg Patients with CKD and > 1g proteinuria, BP goal should be < 125-130/75-80 mmHg
Complications of nephropathy Possible complications of diabetic nephropathy include: hypoglycemia (from decreased excretion of insulin)(insulin isn't secreted by the kidneys) rapidly progressing chronic kidney failure end-stage kidney disease Hyperkalemia Nephrotic syndrome
Complications of nephropathy severe hypertension complications of hemodialysis complications of kidney transplant coexistence of other diabetes complications peritonitis (if peritoneal dialysis used) increased ifections
Diabetic Retinopathy Dot blot – Hemorrhages (Microaneurysms)
Diabetic Retinopathy Pre retinal Hemorrhage - detachment
Diabetic Retinopathy Advanced fibrous plaques
Label the diagram. Hard dep. Optic disc Macula Blot hem Cotton wool 1. 2. 3. 4. 5.
Blood vessel calcification: Amputated thumb
Label the diagram. Capillary Nodule – AGE Bowman caps Hyaline arteriolo sclerosis in arteriole. 1. 2. 3. 4.
Infections in Diabetes: Decreased metabolism – low immunity. Decreased function of lymphocytes & neutrophils – glycosylation. Glycosylation of immune mediators. Ab Capillary thickening – impaired inflammation. Ischemia & infarctions. Increased glucose (alone is not the cause*) Diabetes State of immunosuppression.
Laboratory Diagnosis: Urine glucose - dip-stick –Screening Random or fasting blood glucose (<11) Fasting > 7mmol, Random >11mmol If Fasting level is between 7-11 then OGTT HbA1c - for follow-up, not for diagnosis Fructosamine - for long term maintenance.
Gestational diabetes Gestational diabetes and impaired glucose tolerance (IGT) in pregnancy affects between of all pregnancies and both have been associated with pregnancy complications.
Fasting and 2 hours postprandial venous plasma sugar during pregnancy. Result 2h postprandial Fasting Not diabetic < 145mg/ dl. <100 mg/dl Diabetic >200 mg/ dl. >125 mg/ dl Border line indicates glucose tolerance test. 125-200 mg/dl. 100-125 mg/dl
50-g oral glucose challenge The screening test for GDM, a 50-g oral glucose challenge, may be performed in the fasting or fed state. Sensitivity is improved if the test is performed in the fasting state . A plasma value above one hour after is commonly used as a threshold for performing a 3-hour OGTT. If initial screening is negative, repeat testing is performed at 24 to 28 weeks. 130 - 140 mg/dl
3 hour Oral glucose tolerance test Prerequisites: - Normal diet for 3 days before the test. - No diuretics 10 days before. - At least 10 hours fast. - Test is done in the morning at rest.
3 hour Oral glucose tolerance test Giving 75 gm (100 gm by other authors) glucose in 250 ml water orally
3 hour Oral glucose tolerance test Criteria for glucose tolerance test: The maximum blood glucose values during pregnancy: - fasting 90 mg/ dl, - one hour 165 mg/dl, - 2 hours 145 mg/dl, - 3 hours 125 mg/dl. If any 2 or more of these values are elevated, the patient is considered to have an impaired glucose tolerance test.
Affects of diabetes on pregnancy birth defects or be stillborn. Infants of mothers with preexisting diabetes experience double the risk of serious injury at birth, triple the likelihood of cesarean delivery, and quadruple the incidence of newborn intensive care unit (NICU) admission.
Affects of diabetes on pregnancy Infants born to mothers with GDM are at risk of being both large for gestational age (macrosomic) and small for gestational age. Macrosomia in turn increases the risk of instrumental deliveries (e.g. forceps, ventouse and caesarean section) or problems during vaginal delivery (such as shoulder dystocia).
Affects of diabetes on pregnancy Neonates are also at an increased risk of low blood glucose (hypoglycemia), jaundice, high red blood cell mass (polycythemia) and low blood calcium (hypocalcemia) and magnesium (hypomagnesemia). GDM also interferes with maturation, causing dysmature babies prone to respiratory distress syndrome due to incomplete lung maturation and impaired surfactant synthesis
Affects of diabetes on pregnancy Studies have shown that the offspring of women with GDM are at a higher risk for congenital malformations. women with GDM have a higher risk of preeclampsia spontaneous abortion and congenital malformations in infants
Indications for detection of diabetes in pregnant women Family history of Diabetes Glucose in urine sample History of unexplained prenatal loss History of large baby
Indications for detection of diabetes in pregnant women History of congenitally malformation infant Maternal obesity Maternal age more than 25 years Members of ethnic/racial group with high prevalence of Diabetes Mellitus
Management during pregnancy Quit smoking/alcohol Home blood glucose monitoring Diet control/Folate supplementation Regular exercise Fetal monitoring by ultrasound scan Accurate insulin regimen
Diabetes and Dental health
The Importance of Dental Care With Diabetes Diabetes is a disease that can affect the whole body, including your mouth. Dental care is particularly important for people with diabetes because they face a higher than normal risk of oral health problems due to poorly controlled blood sugars. The less well controlled the blood sugar, the more likely oral health problems will arise. This is because uncontrolled diabetes impairs white blood cells, which are the body's main defense against bacterial infections that can occur in the mouth.
What Dental Problems are You at a higher risk for? Dry mouth, xerostomia and salivary gland dysfunction Caries Increased susceptibility to bacterial, viral and fungal (that is, oral candidiasis) infections Periapical abscesses Periodontitis and loss of teeth Lichen planus Burning Mouth Syndrome Gingivitis
Dry Mouth Uncontrolled diabetes can decrease saliva flow, resulting in dry mouth. Dry mouth can further lead to sores, ulcers, infections, and tooth decay.
Dry Mouth Leads to Ulcers and Sores
Dry Mouth Can… Cause difficulties in tasting, chewing, swallowing, and speaking Increase your chance of developing dental decay and other infections in the mouth Be a sign of certain diseases and conditions Be caused by certain medications or medical treatments
Symptoms Include… A sticky, dry feeling in the mouth Trouble chewing, swallowing, tasting, or speaking A burning feeling in the mouth A dry feeling in the throat Cracked lips A dry, tough tongue Mouth sores An infection in the mouth Decay, when there is not an adequate supply of saliva, the rate of tooth decay increases rapidly
Symptoms Include… The average person creates around 1 Liter of saliva a day. If saliva production is reduced, an individual's oral bacteria levels can increase 10 times over normal levels.
Salivary gland dysfunction and Xerostomia There are reports of dry mouth complaints, which is known as xerostomia, as well as salivary hypofunction in patients with diabetes, which may be due to polyuria, or an underlying metabolic or endocrine problem. When the normal environment of the oral cavity is altered because of a decrease in salivary flow or alteration in salivary composition, a healthy mouth can become susceptible to dental caries and tooth deterioration.
Treatment of Dry Mouth: a high-fluoride toothpaste like Colgate’s Prevident 5000+ to help reduce decay Biotene, an oral rinse found over the counter which relieves of dry mouth. Salagen ( Pilocarpine). Salagen pills have been shown to provide significantly increased saliva flow and relief of dry mouth. Since Salagen may cause fluctuations in blood pressure or heart rate, you should be closely supervised by an M.D.
Treatment of Dry Mouth: Chew gum or sour candy. Look for sugarless gum or candy with Xylitol. If you chew this gum for five minutes after every meal, studies show that you can reduce the incidence of tooth decay up to 62%.
Dental Caries & Cavities It occurs when your teeth are frequently exposed to foods containing carbohydrates such as starches and sugars like soda pop, candy, cake and even sticky fruits. Cavities have been identified as a bacterial infection. Bacteria inhabit the plaque and form up to 500 different
How Cavities Form Plaque interacts with food deposits on your teeth to produce acid that will slowly dissolve the calcium in your teeth. The surface of the tooth..."enamel" is 97% calcium, causing tooth decay and some of the other products cause gum disease and bad breath. When enough calcium dissolves from the tooth surfaces, the surface breaks and forms a hole. That is how cavities form. An active lesion demineralizes the tooth and can be diagnosed based upon color, surface texture and x-rays. White spots can be active lesions if they are not glossy, and feel rough to the explorer.
Cavities An area of decay may take as long as 6-8 years or as short as 6 months to dissolve the outer layer (enamel) of the tooth. If you have a "cavity" this outer layer has collapsed producing a hole that cannot repair itself.
Tooth decay & cavities Root cavities: As you age, your gums can recede, leaving parts of your tooth root exposed. Since there is no enamel covering your tooth roots, these exposed areas easily decay. Most people over 60 have root cavities as a result of gum disease.
Tooth decay & cavities Gum recession has been found to occur more frequently and more extensively in moderate-and poorly-controlled diabetic patients because plaque responds differently, creating more harmful proteins in the gums.
Tooth decay & cavities Repeated decay around existing fillings: Decay can form around existing fillings and crowns. This is because these areas are not as smooth as a natural tooth surface and can decay easier.
Bacterial, Viral and Fungal Infections Thrush, or oral candidiasis, is an infection caused by a fungus that grows in the mouth. People with diabetes are at risk for thrush because the fungus thrives on high glucose levels in saliva. Smoking, taking antibiotics often, or wearing dentures, (especially when they are worn constantly), can also lead to this fungal infection. Medication is available to treat this infection. Good diabetic control, not smoking, and removing and cleaning dentures daily can help prevent thrush.
Periapical Abscesses A dental abscess is an infection of the mouth, face, jaw, or throat that begins as a tooth infection or cavity. Although these infections can be caused by poor dental health and can result from lack of proper and timely dental care, they may also occur in people with underlying autoimmune disorders and people who have other conditions that weaken the immune system (diabetes, post-radiation/chemotherapy cancer care & diabetes). Dental abscesses can also be triggered by minor trauma in the oral cavity.
Periodontitis Diabetics are more prone to the development of gum disease, (periodontal disease), from gingivitis that is caused by the presence of bacteria in plaque
Periodontitis Plaque is the white sticky film that accumulates on teeth both above and below the gum line that can harden into a rough yellow or brown deposit called tartar or calculus.
Any periodontal disease you may develop can be more severe and harder to control Without regular dental checkups, periodontal disease may result if gingivitis is left untreated. It can also cause inflammation and destruction of tissues surrounding and supporting teeth, gums, bone and fibers which hold the gums to the teeth. Gum infections can make it hard to control blood sugar. Once a gum infection starts, it can take a long time to heal. If the infection is severe, teeth can loosen or even fall out.
Periodontitis Facts It has been shown that patients with type 2 diabetes are three times more likely to develop periodontal disease than are people without diabetes. When people with diabetes smoke, they are 20 times more likely to develop periodontitis with loss of supporting bone than are those without diabetes. One-third of people with DM have severe periodontal disease
Diabetes and Periodontitis Periodontal disease has been proposed as the sixth complication of DM; the other five complications are retinopathy, neuropathy, nephropathy, cardiovascular disease and peripheral vascular disease
Lichen Planus Lichen planus is a relatively common, chronic mucocutaneous disease of unknown cause. It generally is considered to be an immunologically mediated process that involves a hypersensitivity reaction on the microscopic level. In the mouth, it looks like lacy white patches on the inside of the cheeks or on the tongue.
Oral Lichen Planus
Causes of Lichen Planus The common causes and risk factor's of Lichen planus include the following:The exact cause is unknown, but the disorder is likely to be related to an allergic or immune reaction.Medical conditions: Medical conditions associated with oral lichen planus include lichen planus of the skin, hypertension, diabetes and peptic ulcers.The disorder has been known to develop after exposure to potential allergens such as medications, dyes, and other chemical substances.
Causes of Lichen Planus The link with diabetes and oral lichen planus is more than likely an adverse affect of the drug therapy used to treat diabetes mellitus.
Burning Mouth Syndrome Patients with burning mouth or burning tongue syndrome usually exhibit no clinically detectable lesions, although the symptoms of pain and burning can be intense. The etiology of burning mouth is varied and often difficult to decipher clinically. Burning mouth syndrome (BMS) is a complex, vexing condition in which a burning pain occurs on your tongue or lips, or over widespread areas involving your whole mouth, without any obvious reason.
BMS The main symptom of burning mouth syndrome is a burning sensation in your tongue, lips, gums, palate or throat. People with the syndrome may describe the sensation in the affected areas as hot or scalded, as if they had been burned with a hot liquid. Other symptoms may include: Dry mouth Sore mouth A tingling or numb sensation in the mouth or on the tip of the tongue A bitter or metallic taste
Gingivitis and Diabetes Gingivitis, a reversible condition, is characterized by inflamed and bleeding gums. Since it can be a precursor to chronic periodontitis, gingivitis requires treatment. In gingivitis, periodontal disease is confined to the gingiva with no loss of junctional epithelial attachment. Gingivitis results from bacterial plaque accumulation at the gum margin and in the sulcus between the margin and the tooth.
Gingivitis and Diabetes Thickening of blood vessels is a complication of diabetes that may increase risk for gum disease. Diabetes causes blood vessels to thicken, which slow the flow of nutrients to the mouth and slows the removal of harmful wastes away from the mouth.
Gingivitis and Diabetes When diabetes is poorly controlled, high glucose levels in mouth fluids may help germs grow and set the stage for gum disease. Smoking increases the risk for gum disease. If you are a smoker with diabetes, age 45 or older, you are 20 times more likely than a person without these risk factors to get severe gum disease, bone loss and tooth loss.
You can do these simple things to help reverse gingivitis and prevent periodontal disease: Diet and exercise may be the most important changes that you can make to improve your quality of life and oral health. Brush your teeth after each meal. Floss daily. Get regular dental cleanings and check-ups. Scrape your tongue with a tongue scraper. Be sure both their medical and dental care providers are aware of your medical history and periodontal status. Be aware of your blood sugar levels, triglycerides and cholesterol levels and have them checked on a regular basis. If your gums bleed while you are brushing your teeth or eating, or a bad taste stays in your mouth, go to the dentist. Tell the dentist about any other changes you see, such as white patches, in your mouth.
When is the best time to receive dental care if you are a diabetic?
Best time to receive dental care Dental procedures should be as short and as stress free as possible.Make morning appointments because blood glucose levels tend to be under better control at this time of day. If you have a scheduled appointment, eat and take your medications as directed. Test your blood sugar level and take your blood pressure and bring these results with you to our office. Be prepared to update your health/dental history at each visit so we can provide you with the best possible care for your condition.
Best time to receive dental care
Best time to receive dental care Postpone non-emergency dental procedures if your blood sugar is not in good control. However, abscesses should be treated right away. See your dentist on a regular basis, every 3 to 4 months, for exams and cleanings. Keep the dentist informed of your health status and if you have any problems controlling your blood sugar. Know that healing time will take longer due to your diabetic condition.