COMPLICATIONS OF DIABETES MELLITUS CHAIR : Dr.B.JAYAKUMAR

COMPLICATIONS OF DIABETES MELLITUSCHAIR : Dr.B.JAYAKUMAR

ACUTE COMPLICATIONS

Hypoglycemia

DKA, HSS

CHRONIC COMPLICATIONS

Microvascular

Macrovascular

HYPOGLYCEMIAIt is a clinical syndrome in which low serum

or plasma glucose levels lead to symptoms of sympathoadrenal activation (sweating, anxiety, tremor, nausea, palpitations, tachycardia) from increased secretion of counterregulatory hormones.

Neuroglycopenia occurs as the glucose level decreases further (fatigue, dizziness, headache, visual disturbances, drowsiness, difficulty speaking, inability to concentrate, abnormal behavior, confusion and loss of consciousness or seizures.

In diabetics a blood glucose <70mg/dL

In diabetics - iatrogenic factors

In non diabetics – fasting

_ postprandial

RISK FACTORS – skipped or insufficient meals, unaccustomed physical exertion, misguided therapy, alcohol ingestion and drug overdose.

Normal & Target Blood Glucose RangesNormal Blood Glucose Levels in People

Who Do Not Have Diabetes

Upon waking—fasting : 70 to 99 mg/dL

After meals : 70 to 140 mg/dL

Target Blood Glucose Levels in People Who Have Diabetes

Before meals : 70 to 130 mg/dL

1 to 2 hours after the start of a meal : <180mg/dL

Source: American Diabetes Association. Standards of Medical Care in Diabetes—2008. Diabetes Care. 2008;31:S12–S54.

Hypoglycemia can also happen during sleep. Some signs of hypoglycemia during sleep include :-

crying out or having nightmares

finding pajamas or sheets damp from perspiration

feeling tired, irritable, or confused after waking up

_Hypoglycemia unawareness - develops when frequent episodes of

hypoglycemia lead to changes in how the body reacts to low blood glucose levels. The body stops releasing the hormone epinephrine and other stress hormones when blood glucose drops too low. The loss of the body’s ability to release stress hormones after repeated episodes of hypoglycemia is called hypoglycemia-associated autonomic failure, or HAAF.

Other medications that can cause hypoglycemia include

salicylates, including aspirin ,

alcohol, warfarin

sulfa medications

pentamidine

tolbutamide, chlorpropamide,

allopurinol, probenecid

TREATMENTOral Glucose

IV Dextrose

Glucagon 1mg IM or SC

PREVENTION –

Patient education

Monitor blood glucose frequently

DIABETIC KETOACIDOSISOccurs in 5% of Pts with Type 1 DM

Precipitating factors – interruption of insulin therapy, infection, trauma, infarction and pregnancy.

Symptoms – polyuria, polydipsia, wt. loss, nausea, vomiting, and vaguely localized abdominal pain.

Signs – dehydration, tachycardia, hypotension, tachypnea, Kussmaul breathing, abdominal tenderness and fruity breath odour.

PathophysiologyRelative or absolute insulin deficiency

combined with counterregulatory hormone excess.

Decreased ratio of insulin to glucagon promotes gluconeogenesis, glycogenolysis and ketone body formation.

Ketone bodies are neutralized by bicarbonates leading to acidosis. Increased lactic acid production also contributes.

DiagnosisHyperglycemia (pregnancy & alcohol

ingestion – euglycemic DKA)

Positive urine ketone

Metabolic acidosis (increased anion gap)

Hyponatremia, hyperkalemia, azotemia

Precipitating infection

ECG

treatmentFluid replacement

Adequate insulin administration

Potassium repletion

Estimate fluid deficit. Average degree of dehydration is 7-9% of body wt. 10% if in hypotension.

Restoration of circulating volume using 0.9% saline.

Replenish total body water deficits.

Maintenance fluid replacement.

IV bolus of regular insulin at 0.15 unit/kg followed by infusion at 0.1unit/kg/hr.

A decrease in blood glucose of 50-75mg/dL/hr is appropriate.

Lesser decrements – insulin resistance

Rapid correction – osmotic encephalopathy

5% dextrose in saline should be infused once plasma glucose reduces to 250mg% and insulin infusion reduced to 0.05unit/kg/hr.

Give the first SC injection of insulin approximately 30min before stopping the infusion.

Potassium infusion at the rate of 10-20mEq/hr except in patients with hyperkalemia, renal failure or oliguria.

Hypokalemia – 40mEq/hr

Bicarbonate therapy – in shock or coma, severe acidosis, severe depletion of plasma bicarbonate, acidosis induced cardiac or respiratory dysfunction or severe hyperkalemia.

IV Antibiotics

Monitoring – Hourly blood glucose, serum electrolytes 2 hourly and ABG as required.

Complications of DKALactic acidosis

Arterial thrombosis – stroke, MI or ischemic limb

Cerebral edema

Rebound ketoacidosis

Hyperglycemic hyperosmolar stateOccurs primarily in Pts with Type 2 DM.

Less common than DKA : incidence of <1case per 1000 person-years.

Prototypical Pt is an elderly individual with type 2 DM, with a several week history of polyuria, wt loss and decreased oral intake that culminates in mental confusion, lethargy or coma.

Signs – profound dehydration, hypotension, tachycardia, altered mental status.

No nausea, vomiting, abdominal pain or Kussmaul’s respiration.

Precipitating factors – stress, infection, stroke, non compliance with medications, dietary indiscretion, and alcohol and cocaine abuse

Pathophysiology – relative insulin deficiency and inadequate fluid replacement.

Insulin def increases hepatic glucose production and impairs glucose utilization.

Hyperglycemia induces osmotic diuresis that leads to intravascular vol depletion, which is exacerbated by inadequate fluid replacement.

DiagnosisHyperglycemia, often >600mg/dL

Plasma osmolality >320 mOsm/L

Absence of ketonemia

pH >7.3

Serum bicarbonate >20 mEq/L

DD – hypoglycemia, hyponatremia, severe dehydration, uremia, hyperammonemia, drug overdose and sepsis.

treatmentFluid therapy – 10-12 L positive fluid balance

over 24-36hrs.

Insulin therapy – IV bolus of 5-10 units, followed by continuous infusion of 0.1-0.15 units/kg/hr. Once plasma glucose reduces to 200-300 mg/dL, insulin infusion can be decreased to 1-2 units/hr. 5% dextrose should be added.

IV antibiotics

Monitoring of therapy – blood glucose every 30-60 min and serum electrolytes every 1-2 hrs.

COMPLICATIONS – thromboembolic events, cerebral edema, adult respiratory distress syndrome, rhabdomyolysis.

LACTIC ACIDOSISWhen there is lack of oxygen in blood,

mitochondria cannot burn all the pyruvate produced by glycolysis; pyruvate accumulates in the cell which is converted to lactate causing lactic acidosis.

Signs – deep and rapid breathing, vomiting and abdominal pain

COHEN-WOODS CLASSIFICATION

TYPE A – reduced perfusion or oxygenation

TYPE B – B1 – underlying disease

- B2 – medication or intoxication

- B3 – inborn error of metabolism

CausesGenetic – MELAS, Glycogen storage diseases

Drugs – Phenformin, Metformin, INH toxicity,

Nucleoside Reverse Transcriptase Inhibitors

Potassium cyanide

Others – hypoxia and hypoperfusion, hemorrhage

Ethanol toxicity, sepsis, shock, hepatic disease

DKA, muscular exercise, renal hypoperfusion

Non Hodgkin's and Burkitts lymphoma

S. pH - <7.35

Lactate levels >5

TREATMENT -

IV line – fluid repletion

Treat cause

Bicarbonate therapy –starting dose one third to half of calculated HCO3 deficit

HCO3 deficit = 0.5 x wt in kg x (desired HCO3 – measured HCO3)

ACUTE SEPSISSepsis is a response to infections that can

lead to widespread inflammation and blood clotting.

CAUSES – urinary tract infection

- pelvic infections

- peri odontic infections

- skin and soft tissue infections

- respiratory tract infections

People with diabetes and sepsis were more likely to develop acute renal failure than people without diabetes, whereas they were less likely to develop acute respiratory failure.

Chronic complicationsMICROVASCULAR –

Eye disease – diabetic retinopathy

- macular edema

Neuropathy – sensory and motor

- autonomic

Nephropathy

MACROVASCULAR –

Coronary artery disease

Peripheral arterial disease

Cerebrovascular disease

OTHER –

Gastrointestinal, genitourinary, dermatologic

Infections

Cataracts, glaucoma, periodontal disease

Mechanisms of complications1) Increased intracellular glucose leads to the formation of advanced glycosylation end products (AGEs), which cross-link proteins, accelerate atherosclerosis, promote glomerular dysfunction, reduce nitric oxide synthesis, induce endothelial dysfunction, and alter extracellular matrix composition and structure.

2) Hyperglycemia induces metabolism of glucose via sorbitol pathway. Increased sorbitol conc. alters redox potential, increases cellular osmolality, generates reactive oxygen species and leads to other types of cellular dysfunction.

3) Hyperglycemia increases the formation of diacylglycerol leading to activation of protein kinase C, which alters the transcription of genes for fibronectin, type IV collagen, contractile proteins, and extracellular matrix proteins in endothelial cells and neurons.

4) Hyperglycemia increases flux through the hexosamine pathway, which may alter function by glycosylation of proteins or by changes in gene expression of TGF-B or PAI-1.

Clinical trialsThe Diabetes Control and Complications Trial

(DCCT) – multicentric clinical trial – 1400 individuals with type 1 DM.

Intensive and conventional diabetes management groups.

Prospective evaluation of development of retinopathy, neuropathy and nephropathy.

Intensive groupConventional groupMultiple administrtn of insulin

Extensive educational, psychological and medical support.

Goal – normoglycemia

Reduction in HbA1c – 7.3%

Twice daily insulin injections.

Quarterly nutritional, educational and clinical evaluatn.

Preventn of symptoms

9.1%

ResultsImprovement of glycemic control reduced

proliferative and non proliferative retinopathy (47%), microalbuminuria(39%), clinical nephropathy(54%), and neuropathy(60%).

If all complications of diabetes were combined, individuals in the intensive group would experience 15.3 more years of life without significant complications.

The United Kingdom Prospective Diabetes Study (UKPDS) – studied the course of >5000 individuals with type 2 diabetes for >10yrs.

Newly diagnosed individuals with type 2 DM were randomized to (1) intensive management using various combinations of insulin and OHA; or (2) conventional therapy using dietary modification and pharmacotherapy. Also randomly assigned to different antihypertensive regimens.

ResultsEach percentage point reduction in A1c was

associated with 35% reduction in microvascular complications.

Strict blood pressure control significantly reduced both microvascular and macrovascular complications.

Kumamoto study – small trial of lean Japanese individuals with type2 DM randomized to either intensive glycemic control or standard therapy with insulin.

Reduction in risk of nephropathy and retinopathy .

DIABETIC RETINOPATHYDM is the leading cause of blindness in US.

Diabetic retinopathy has four stages:

Mild Nonproliferative Retinopathy. At this earliest stage, microaneurysms occur. They are small areas of balloon-like swelling in the retina's tiny blood vessels.

Moderate Nonproliferative Retinopathy. As the disease progresses, some blood vessels that nourish the retina are blocked.

Severe Nonproliferative Retinopathy. Many more blood vessels are blocked, depriving several areas of the retina with their blood supply. These areas of the retina send signals to the body to grow new blood vessels for nourishment.

Proliferative Retinopathy. At this advanced stage, the signals sent by the retina for nourishment trigger the growth of new blood vessels. This condition is called proliferative retinopathy. These new blood vessels are abnormal and fragile. They grow along the retina and along the surface of the clear, vitreous gel that fills the inside of the eye. By themselves, these blood vessels do not cause symptoms or vision loss. However, they have thin, fragile walls. If they leak blood, severe vision loss and even blindness can result.

Osmotic stress from sorbitol accumulation has been postulated as an underlying mechanism in the development of diabetic microvascular complications, including diabetic retinopathy.

Duration of DM and degree of glycemic control are the best predictors of development of retinopathy.

TreatmentMost effective therapy – prevention –

intensive glycemic and blood pressure control.

Annual examination by ophthalmologist.

Proliferative retinopathy – panretinal laser photocoagulation

MACULAR EDEMA - swelling of retina in diabetes due to

leaking of fluid from blood vessels within the macula.

As macular edema develops, blurring develops in the middle or just to the side of the central visual field.

Lifetime risk to develop macular edema in diabetics is 10%.

Visual loss from macular edema can progress over mths.

The condition is closely related with the degree of diabetic retinopathy.

Hypertension and fluid retention are other factors.

Fluid retention is mainly caused by loss of protein in urine.

Classified into focal and diffuse types

Focal – caused by foci of vascular abnormalities primarily microaneurysms which tend to leakage fluid.

Diffuse – caused by dilated retinal cappilaries in the retina

TreatmentFocal – Focal laser treatment – to close

leaking microaneurysms

Diffuse – Grid laser treatment – produce retinal burn of mild to moderate intensity

Patient is rechecked several mths after treatment and if not responding, laser treatment is repeated.

Goal of treatment is to reduce chances of progressive visual loss. Visual acuity does not improve.

TRIALSDIABETIC RETINOPATHY STUDY (DRS)

Scatter photocoagulation significantly reduces the risk of severe visual loss from proliferative diabetic retinopathy.

EARLY TREATMENT DIABETIC RETINOPATHY STUDY (ETDRS)

Focal photocoagulation reduces risk of moderate visual loss by 50% or more

DIABETIC RETINOPATHY VITRECTOMY STUDY (DRVS)

It provided guidelines for the most opportune time for vitrectomy surgery for patients with type 1 and 2 diabetes who suffered from vitreous hemorrhage or from severe PDR in eyes with useful vision.

DIABETIC RETINOPATHY CANDESARTAN TRIALS (DIRECT)

Candesartan compared to placebo reduces the progression of diabetic retinopathy in normotensive, normoalbuminuric patients with type 1 diabetes and retinopathy. An 18% reduction in incidence was observed.

DIABETIC NEUROPATHYDiabetic neuropathy occurs in approx. 50% .

Polyneuropathy, mononeuropathy and/or autonomic neuropathy.

Correlates with duration of diabetes and glycemic control.

Risk factors – increased BMI, smoking, cardiovascular disease, elevated triglycerides, hypertension.

Nerve damage is likely due to a combination of factors:

1) metabolic factors, such as high blood glucose, long duration of diabetes, and possibly low levels of insulin

2) neurovascular factors, leading to damage to the blood vessels that carry oxygen and nutrients to nerves

3) autoimmune factors that cause inflammation in nerves

4) mechanical injury to nerves, such as carpal tunnel syndrome

5) inherited traits that increase susceptibility to nerve disease

6) lifestyle factors, such as smoking or alcohol use

ADA recommends screening for distal symmetric neuropathy beginning with the initial diagnosis of diabetes and for autonomic neuropathy 5 years after diagnosis of type1 DM and at the time of diagnosis of type2 DM. Then screened annually for both forms of neuropathy.

PolyneuropathyMost common form of diabetic neuropathy is

distal symmetric polyneuropathy.

Symptoms – distal sensory loss, sensation of numbness, tingling, sharpness or burning sensation in the feet that spreads proximally.

O/E – sensory loss, loss of ankle reflexes and abnormal position sense.

Sensorimotor diabetic peripheral polyneuropathy is a major risk factor for foot trauma, ulceration and Charcot arthropathy; and is responsible for 50 – 75% of non- traumatic amputations.

Neuropathic pain develops in some individuals.

Pain typically involves the lower extremities, is usually present at rest and worsens at night.

Both acute and chronic form

As diabetic neuropathy progresses, pain disappears but a sensory deficit in the lower extremities persists.

PolyradiculopathyDiabetic polyradiculopathy is a syndrome

characterised by severe disabling pain in the distribution of one or more nerve roots.

It may be accompanied by motor weakness.

Intercostal or truncal radiculopathy causes pain over thorax and abdomen.

Involvement of lumbar plexus or femoral nerve causes severe pain in the thigh or hip and maybe associated with muscle weakness in the hip flexors or extensors ( diabetic amyotrophy ).

Usually self-limiting and resolve over 6-12 mths.

MononeuropathyDysfunction of isolated cranial or peripheral

nerve.

Vascular etiology suggested, pathogenesis unknown.

3rd cranial nerve most common – diplopia, ptosis, ophthalmoplegia with normal pupillary constriction to light.

Sometimes IV, VI or VII are affected.

Autonomic neuropathyLongstanding diabetics develop autonomic

dysfunction involving cholinergic, noradrenergic and peptidergic systems.

Can involve cardiovascular, gastrointestinal, genitourinary, sudomotor and metabolic systems.

Resting tachycardia and orthostatic hypotension.

Hyperhidrosis of upper extremities and anhidrosis of lower extremities result from sympathetic nervous system dysfunction.

Hypoglycemia unawareness due to reduced counterregulatory hormone release.

TreatmentScreening – sensation in the lower

extremities should be documented at least annually, using either a light-touch monofilament or a tuning fork of frequency 128Hz.

Symptoms of diabetic neuropathy may not necessarily improve.

Risk factors for neuropathy should be treated.

Avoidance of neurotoxins (alcohol) and smoking, supplementation with vitamins for possible deficiencies and symptomatic treatment.

Patients should check their feet daily and take precautions to prevent calluses or ulcer formation.

Chronic painful neuropathy may respond to

TCAs – Amitryptyline, nortryptyline, imipramine, desipramine

SSRIs – duloxetine

Anticonvulsants – gabapentin, pregabalin, carbamazepine, lamotrigine

Duloxetine and pregabalin are approved by the U.S. Food and Drug Administration specifically for treating painful diabetic peripheral neuropathy

Since the pain may resolve over time, medications may be discontinued as progressive neuronal damage occurs

Orthostatic hypotension – non-pharmacologic measures like adequate salt intake, avoidance of dehydration and diuretics, and lower extremity support hose.

Fludrocortisone (0.1-0.3mg/day), midodrine, clonidine, octreotide, yohimbine

TRIALSJOURNAL OF AMERICAN MEDICAL ASSOCIATION DEC 2 , 1998

Gabapentin for the Symptomatic Treatment of Painful Neuropathy in Patients with

Type 2 DM

Randomized, double blind, placebo controlled, 8week trial between July ‘96

and March ‘97

RESULTS – Gabapentin treated patients daily score at the study end point was significantly lower (P<.001) compared with placebo treated patients end point

score

DIABETESCAN AUGUST 1999

Treatment of diabetic polyneuropathy with the antioxidant alpha-lipoic acid : a 7 mth multicentric randomized trial (ALADIN III) Alpha lipoic acid in diabetic neuropathy

RESULTS – No significant differences

NEUROLOGY MARCH 25, 2003

Controlled release Oxycodone for pain in diabetic neuropathy

Multicentric, randomized, double blind, placebo controlled, parallel group study for 6 weeks

RESULTS – At an average dose of 37mg/day, CR Oxycodone provided more analgesia than placebo.

NEUROLOGY 2001

Lamotrigine reduces painful diabetic neuropathy

Randomized, placebo controlled trial over 6 weeks

RESULTS – Global assessment of efficacy favored lamotrigine treatment over placebo

NEUROLOGY DEC 2004

Pregabalin relieves symptoms of Painful Diabetic Neuropathy

Multicentric, randomized, double blind, placebo controlled study

RESULTS – Patients in Pregabalin group showed improvement in end point mean pain score vs. placebo

DIABETIC NEPHROPATHYLeading cause of DM related morbidity and

mortality.

20 – 40% of diabetics develop nephropathy

Smoking accelerates decline in renal function

Family history of diabetic nephropathy is a known risk factor.

Pathogenesis involves the effects of soluble factors (growth factors, angiotensin II, endothelins), hemodynamic alterations in the renal microcirculation (glomerular hyperfiltration or hyperperfusion, increased glomerular capillary pressure) and structural changes in the glomerulus (increased EC matrix, basement membrane thickening, mesangial expansion, fibrosis).

In the first years – glomerular hyperperfusion and renal hypertrophy occur with increase in GFR.

During first 5 yrs – thickening of the glomerular basement membrane, glomerular hypertrophy and mesangial volume expansion occurs.

After 5-10 yrs – approx. 40% develop microalbuminuria

MICROALBUMINURIA –

is defined as 30-300 mg/d in a 24 hr collection or 30-300mcg/mg creatinine in a spot collection (preferred method).

Approx. 50% progress to macroalbuminuria over the next 10 yrs.

There is a steady decline in GFR and approx. 50% reach ESRD in 7-10 yrs.

Once macroalbuminuria develops, blood pressure rises slightly and the pathologic changes are likely irreversible.

Type 2 DM v/s type 1 DM

1) present at diagnosis

2) hypertension more common

3) microalbuminuria less predictive – maybe secondary to hypertension, CHF, prostate disease or infection

Type IV renal tubular acidosis (hyporeninemic hypoaldosteronism) may occur in type 1 or 2 DM – propensity to develop hyperkalemia.

Predisposed to radiocontrast induced nephrotoxicity. Risk factors – preexisting nephropathy and volume depletion. Individuals with DM should be well hydrated before and after dye exposure, and the s.Cr should be monitored for 24 hrs.

Screening for microalbuminuria should be performed in patients with type 1 DM >5 yrs, in patients with type 2 DM and during pregnancy.

Other conditions that might increase microalbuminuria are UTI, hematuria, heart failure, febrile illness, severe hyperglycemia, severe hypertension and vigorous exercise.

Treatment1) Normalization of glycemia

2) Strict blood pressure control

3) Administration of ACEIs or ARBs

Improved glycemic control reduces the rate at which microalbuminuria appears and progresses.

Blood pressure should be maintained at <130/80 mmHg in diabetic individuals without proteinuria. A slightly lower blood pressure for those with microalbuminuria.

ACEIs or ARBs should be used to prevent progression. The drug dose is increased after 2-3 mths of therapy till microalbuminuria disappears or max. dose reached.

If not possible, Ca channel blockers, beta blockers or diuretics should be used.

ADA suggests modest restriction of protein intake in microalbuminuria – 0.8g/kg/day and <0.8g/kg/day.

Nephrology consultation when the estimated GFR < 60ml/min/1.743m2.

Hemodialysis in patients with DM is associated with more frequent complications such as hypotension (due to autonomic neuropathy or loss of reflex tachycardia), more difficult vascular access and accelerated progression of retinopathy.

Atherosclerosis is the leading cause of death in patients on dialysis.

Renal transplant from a living related donor is the preferred therapy, but requires chronic immunosuppression.

Combined pancreas-kidney transplant offers the promise of normoglycemia and freedom from dialysis.

TRIALS

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