Diabetes Mellitus Type 2

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Diabetes MellitusType 2

• 8 of adult population

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Presentation

• Fatigue
• Weight loss
• The three Ps
• Blurred vision
• Infections
• Muscle cramps
• Poor healing

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Diagnosis of Diabetes
Also a random glucose gt200 mg/dL symptoms of
hyperglycemia
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Metabolic syndrome(a.k.a. Syndrome X)

• ? Definition (ATP III vs WHO)
• ? Name cardiometabolic risk
• Associated with an increased risk of diabetes,
  cardiovascular and overall mortality
• Abdominal obesity
• Dyslipidemia (low HDL, hypertriglyceridemia)
• Impaired glucose metabolism (Fasting glucose
  gt100mg/dl)
• Hypertension

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Metabolic Syndrome

• WHO
• FPG gt 110 mg/dl 2 of the following
• Waist/hip ratio gt.9 or abdominal Girth gt 37
  inches
• HDL lt 35mg/dl Triglyceridesgt150mg/dl
• BP gt 140/90

• ATP III
• 3 of the following
• Abdominal girth gt40 inches in men
  gt35 inches in women
• HDL lt 40 mg/dl in men lt 50 mg/dl in women
• Triglycerides gt150 mg/dl
• BPgt 130/85
• FPG gt 100 mg/dl

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Screening for Diabetes
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Classifications

• Type1
• lt10 of Diabetics
• Normal to underweight
• Age of onset lt40, peaking at 14
• abrupt onset of symptoms
• Pathogenesis is insulin deficiency (B-cell
  destruction)
• Diabetic ketoacidosis

• Type 2
• gt90 of Diabetics
• Obese patients
• Age of onsetgt40
• Gradual onset of symptoms
• pathogenesis is insulin resistance others
• Non-ketotic hyperosmolar syndrome

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Treatment

• Patient Education
• Lifestyle modification
• exercise
• risk reduction
• diet
• disease monitoring
• Pre-prandial vs post-prandial testing
• Recognition and treatment of hypoglycemia

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Diabetic Diet

• Individualized, there is no standard ADA diet.
• Limit total (20-30) and saturated fats (lt10)
• Limit carbohydrates to achieve desired weight
  loss (250-500 cal below calculated needs)
• The amount and not the source is important
• Calorie exchanges to tailor diet to medications
• Limit protein if nephropathy exits

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Hypertension in Diabetes

• ACE inhibitor
• Primary prevention of diabetic nephropathy
• Secondary prevention
• decrease proteinuria
• slows the decline of the GFR
• May improve insulin sensitivity
• Cardiovascular benefits (CAPP, HOPE, ABCD)
• Need to watch for the development of hyperkalemia
  associated with hyporenin hypoaldosteronism

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Hypertension in Diabetes

• Angiotensin II receptor blockers
• NEJM Sept.2001
• Renal protective, with some evidence of
  cardiovascular benefits (LIFE, diabetes subgroup
  analysis)
• May be appropriate first line agent in type II
• Calcium channel blockers
• non-dihydropyridines (verapamil, diltiazem)
• prevention of diabetic nephropathy?
• neutral effect on glucose tolerance and lipids

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Hypertension in Diabetes

• Despite concerns regarding diuretics and
  B-blockers propensity to worsen glucose control
  and adversely effect lipids, they have been
  shown to be safe and effective in controlling BP
  in diabetics.
• B-blockers can also mask the adrenergic symptoms
  of hypoglycemia
• What is your blood pressure goal?

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130/80
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Tight Blood Pressure Control in Diabetes

• UKPDS- tight control defined as lt150/85
• Actual average blood pressures were 144/82 vs
  154/87
• Associated with lower stroke, retinopathy and
  Diabetic related deaths
• HOT study-diastolic BP goal of 80
• Resulted in lower cardiovascular deaths and
  events compared with goal of 90.
• ABCD trial-128/75 achieved BP
• Tight BP control associated with lower overall
  mortality 5.5 vs 10.7 for moderate control
  (137/81)

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Tight control of Blood Pressure vs Tight Control
of Blood Sugar
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Model of Multihormonal Regulationof Glucose
Homeostasis

• Incretin
• Mimetics
• GLP-1 analogs
• Exenatide

Brain
Liver
Metformin
Stomach
PostprandialGlucagon
Rate ofglucoseappearance
Alpha- glucosidase inhibitors
Plasma Glucose
Rate ofglucosedisappearance
Insulin

• Amylin analogs
• Pramlintide

TZDs
Pancreas
Tissues
Insulin Secretagogues
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Oral Sulfonylureas

• First generation (chlorpropamide, tolazamide,
  tolbutamide)
• Second generation
• Glyburide 2.5-20 mg a day
• Gypizide 5-40mg a day
• Glimepiride 1-8 mg a day
• Stimulates pancreatic insulin secretion
• side effects weight gain, hypoglycemia, Sudden
  death?

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Biguanides

• Metformin (Glucophage)
• Recommended as initial treatment of type 2
  diabetes
• 500 mg BID to start, max dose 2500 mg a day
• mechanism of action
• decrease hepatic gluconeogenesis
• improve peripheral insulin resistance
• side effects
• GI diarrhea, cramps, nausea
• Sustained release agents decrease G.I. Side
  effects
• lactic acidosis

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Biguanides

• Lactic acidosis
• Less common than phenformin
• Usually associated with CHF, renal
  insufficiency, liver disease, hypoxia, Etoh
  abuse, IV contrast dye.
• Black box warning avoid in CHF and CKD
  (creatininegt1.5 in men, 1.4 in women)
• Doesnt cause weight gain
• hypoglycemia is rare

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Thiazolidinediones

• Trogltazone (Rezulin)
• Pulled from the market March , 2000 due to
  hepatotoxicity
• Rosiglitazone (Avandia)
• 4-8 mg/day (daily or BID)
• Pioglitazone (Actos)
• 15-45 mg/day

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• Work by improving peripheral insulin sensitivity
• can be used as mono-therapy or with other oral
  agents. (caution with insulin)
• Maintains beta cell function
• Pioglitizone with lipid benefits (raise HDL,
  lower triglycerides)
• Side effects include
• weight gain (12bs)
• possible liver toxicity
• increase plasma volume (caution with CHF)
• ? Increase cardiovascular risk in Rosiglitizone

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Meglitinides

• Repaglinide (Prandin)
• Nateglinide (Starlix)
• Stimulates 1st phase pancreatic insulin secretion
  (rapid and short acting)
• short half-life
• Take 15-30 minute prior to eating
• no insulin stimulation between mealsless weight
  gain

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Alpha-glucosidase Inhibitor

• Acarbose (Precose), miglitol (Glyset)
• delays carbohydrate digestion
• reduces postprandial hyperglycemia
• 25-100 md T.I.D.
• Side effects
• abdominal pain, bloating, flatulence

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GLP-1 Modes of Action in Humans

• Stimulates glucose-dependent insulin secretion

• Suppresses glucagon secretion

• Slows gastric emptying

GLP-1 is secreted from the L-cells in the
intestine

• Reduces food intake

• Improves insulin sensitivity

Long term effectsdemonstrated in animals
This in turn

• Increases beta-cell mass and maintains
  beta-cell efficiency

Drucker DJ. Curr Pharm Des 2001
71399-1412Drucker DJ. Mol Endocrinol 2003
17161-171
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Incretin mimetic

• Byetta (exenatide)
• Subcutaneous injection BID
• Mechanism of action
• Stimulates the GLP-1 receptors
• Stimulates insulin release in response to meals
• Inhibits release of glucagon
• Slows GI absorption, reduces food intake
• Improves insulin sensitivity, maintains beta-cell
  function
• Side effects
• Nausea
• Pancreatitis

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• Januvia (sitagliptin)
• Prolongs the action of Incretins
• Inhibits DPP-4 enzyme
• 100 mg once a day dosing
• Requires renal dosing-50mg if GRFlt60, 25 mg if
  lt30
• Well tolerated
• No weight gain, hypoglycemia or GI disturbance

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Mechanism of Action of Sitagliptin (Januvia)
Glucose dependent
? Insulin (GLP-1andGIP)
? Glucose uptake by peripheral tissue
Ingestion of food
Pancreas
Release of active incretins GLP-1 and GIP
Beta cells Alpha cells
? Blood glucose in fasting and postprandial states
GI tract
X
Glucose- dependent
DPP-4 enzyme
Sitagliptin (DPP-4 inhibitor)
? Hepatic glucose production
? Glucagon (GLP-1)
Inactive GLP-1
Inactive GIP

• Incretin hormones GLP-1 and GIP are released by
  the intestine throughout the day, and their
  levels ? in response to a meal.

In healthy subjects, sitagliptin did not lower
blood glucose or cause hypoglycemia
GLP-1glucagon-like peptide-1 GIPglucose-depende
nt insulinotropic polypeptide.
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Amylin Analogue

• Symlin (pramlintide)
• Synthetic analogue of beta cell hormone
• Reduces postprandial glucagon secretion
• Increases satiety, slows gastic emptying
• Containdicated in patients with gastroparesis
• Dosed q AC
• Can cause hypoglycemia

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Insulin
Short acting (regular, Lispo) Intermediate (NPH,
lente) mixture 70/30, 75/25 Long acting
(ultalente, lantus)
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Approximate Pharmacokinetic Profiles of Human
Insulin and Insulin Analogues
Hirsch, I. B. N Engl J Med 2005352174-183
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New Insulins

• Lispro/Aspart/Apidra
• Shorter onset and duration of action than R
• less hypoglycemia
• treat postprandial hyperglycemia
• Glargine (Lantus)/Determir (Levemir)
• steady duration of action for 24 hours
• peakless release
• less hypoglycemia

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Insulin regimens
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Standard Regimen
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Poor mans Insulin Pump
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Long term complications

• Retinopathy
• Neuropathy
• Nephropathy
• Arteriosclerosis

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Retinopathy

• Diabetics are also at increased risk of cataracts

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Non-proliferative Retinopathy
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• Also called background retinopathy
• can develop in as early as 3-5 years
• see microaneurysms, dot-blot hemorrhages, hard
  exudates
• usually does not lead to blindness

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Proliferative Retinopathy
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• Occurs in Response to retinal ischemia (cotton
  wool exudates)
• neo-vascularization
• vitreous hemorrhages can result
• Fibro-proliferative changes result in retinal
  traction and detachment if the hemorrhage is not
  treated.

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Treatment

• Prevention
• Primary and secondary
• strict glycemic control (Hgb A1clt7.0)
• strict blood pressure control (? additional
  benefit from ACE inhibitors)
• Secondary
• avoid strenuous activities to prevent hemorrhage
• photocoagulation
• vitrectomy
• Required after a hemorrhage to avoid permanent
  blindness

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Nephropathy
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• Develops in 35-45 of all diabetics (type 1 and
  2)
• Hypertension and poor glycemic control will
  accelerate the process
• Progression from microalbuminuria to end stage
  renal failure

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Microalbuminuria

• 30-300mg of albumin per 24 hours
• random albumin-to-creatinine ratio preferred
  diagnostic test
• can occur as early as 5 years after the onset of
  Diabetes
• also a risk factor for cardiovascular disease and
  early mortality from cardiovascular disease

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Proteinuria

• Greater than 300mg/day of albumin
• detectable on a dipstick urinalysis
• renal function is typically preserved (may
  actually have glomerular hyper-filtration and
  super-normal creatinine clearance)
• usually associated with the onset of hypertension
  in type 1 (type 2 patients frequently have
  essential hypertension in addition to their
  diabetes)

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Nephrotic Syndrome

• gt3.5 grams of protein /24 hours
• associated with falling GFR
• development of peripheral edema
• usually seen 5-10 years after the development of
  proteinuria

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Treatment of nephropathy

• Primary Prevention
• strict glycemic control (Hgb A1clt7.0)
• Diabetes Control and Complications Trial
• Ace inhibitors, ARBs
• Secondary Prevention
• strict glycemic control (Hgb A1clt7.0)
• Ace inhibitors, ARBs
• strict blood pressure control 130/80
• 125/75 if renal insufficiency

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Neuropathy

• Peripheral sensory-motor neuropathy
• symptoms
• symmetrical stocking glove distribution
• numbness, paresthesia, dysesthesia
• early signs
• decrease sensation (mono-filament test)
• decrease Achilles reflex
• decrease vibratory sensation

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Treatments

• Prevention (primary and secondary)
• strict glycemic control (HgbA1clt7.0)
• Pain medications
• Antidepressants
• TCAs, duloxetine (Cymbalta)
• seizure medications
• carbamazepoine, phenytoin, gabapentin, pregabalin
  (Lyrica)
• topical preparations
• capsacin

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Neuropathy

• Motor
• cranial neuropathy (III,IV,VI)
• peripheral neuropathy
• Median nerve
• foot drop

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Autonomic Neuropathy

• Gastroparesis
• Diarrhea/constipation
• Orthostasis/resting tachycardia
• Impotency/retrograde ejaculation

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Arthrosclerosis

• Cerebral Vascular Disease
• Coronary Vascular Disease
• Peripheral Vascular Disease
• Impaired Lipid Profile
• Elevated Triglycerides
• Low HDL
• Small Dense athrogenic LDL particles

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Recommendations

• Strict glycemic control (ADA)
• HgbA1clt7.0 (AACE recommends lt6.5)
• Pre-prandial glucose 90-130mg/dl
• 1-2hr post-prandial sugars lt180mg/dl
• Requires motivated and compliant patients
• Strict blood pressure control
• lt130/80
• Use ACE inhibitors/ARBs 1st line
• Annual Eye examinations
• Annual micro-albumin checks

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Recommendations

• Tight lipid management
• LDLlt100 mg/dl
• Patients age gt40 use statins to lower LDL by
  30-40
• Goal lt 70mg/dl Prove It trial
• Triglycerideslt150 mg/dl
• HDLgt40 mg/dl in men and gt50 mg/dl in women
• Foot checks at each office visit
• Aspirin therapy recommended for all diabetics