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Sugar DisordersSugar Disorders

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SUGAR DISORDERSSUGAR DISORDERS

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DM (2008: 8 percent of the U.S. population has diabetes.)

15.8 million (2005)15.8 million (2005) T1- 1 millionT1- 1 million T2-14.8 millionT2-14.8 million ‘‘Other’ DM-<20,000Other’ DM-<20,000 2008: 24 million, an increase of more than 3 million in two 2008: 24 million, an increase of more than 3 million in two

years (2007)years (2007)

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T1 and T2 Features

T1: (10% of cases)T1: (10% of cases) immune mediated 90%immune mediated 90% DKA+++DKA+++ Children and under 20 Children and under 20

(15/100,000)(15/100,000) Absent insulinAbsent insulin Increased GlucagonIncreased Glucagon Insulin antibodiesInsulin antibodies FH+FH+ ?virus: rubella/ coxsackie/?virus: rubella/ coxsackie/ cow’s milkcow’s milk

T2: (90% of cases)T2: (90% of cases) DKA absentDKA absent Genetics- insulin resistance and Genetics- insulin resistance and

Beta cell loss (chr.2- in Hispanics)Beta cell loss (chr.2- in Hispanics) High insulin levelsHigh insulin levels Gut Obesity#1 causeGut Obesity#1 cause ? leptin and ? leptin and

adiponectinadiponectin

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Metabolic SyndromeSyndrome X (Insulin resistance Syndrome)

Increased TGL (triglycerides)Increased TGL (triglycerides) Decreased HDL (high density lipoproteins – the good kind)Decreased HDL (high density lipoproteins – the good kind) HTN (hypertension)HTN (hypertension) Increased LDL (low density lipoproteins – bad kind)Increased LDL (low density lipoproteins – bad kind) Increased Uric AcidIncreased Uric Acid Truncal obesity (aka central obesity)Truncal obesity (aka central obesity) Increased clotting tendency and pro-inflammatory stateIncreased clotting tendency and pro-inflammatory state

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Clinical Features of DM

T1T1 T2T2

Polyuria and thirstPolyuria and thirst ++++ ++

Weakness or FatigueWeakness or Fatigue ++++ ++

Polyphagia and Weight loss Polyphagia and Weight loss ++++ --

Recurrent blurred visionRecurrent blurred vision ++ ++++

Vulvovaginitis or pruritusVulvovaginitis or pruritus ++ ++++

Peripheral neuropathyPeripheral neuropathy ++ ++++

Nocturnal enuresisNocturnal enuresis ++++ --

Often asymptomaticOften asymptomatic -- ++++

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T2 diabetics

Waist to Hip ratio-Waist to Hip ratio-Men greater than 0.9Men greater than 0.9Women greater than 0.8Women greater than 0.8

Indicates increased risk of diabetes in obese peopleIndicates increased risk of diabetes in obese people

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Current Blood Sugar Numbers

NormalNormal ImpairedImpaired DiabetesDiabetesMellitusMellitus

Fasting plasma Fasting plasma glucoseglucose

Less thanLess than100 mg/dL100 mg/dL

100-125100-125mg/dLmg/dL

≥≥126 mg/dL*126 mg/dL*

Two hours after Two hours after glucose loadglucose load

≤ ≤ 140 mg/dL140 mg/dL ≥≥140-199 mg/dL140-199 mg/dL ≥ ≥ 200 mg/dL200 mg/dL

*126 or more on 2 occasions is diagnostic*126 or more on 2 occasions is diagnostic

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Glycated Hemoglobin A1c

Normal HgbA1c is 4-6%Normal HgbA1c is 4-6% Abnormally elevated in diabeticsAbnormally elevated in diabetics Reflects blood sugar levels over past 8-12 weeksReflects blood sugar levels over past 8-12 weeks If the value is greater than 2% then drug dose If the value is greater than 2% then drug dose

adjustments can be doneadjustments can be done

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Lipid abnormalities in DM

In T1 patients initial LDL is high but returns to normalIn T1 patients initial LDL is high but returns to normal In T2 patients- TGL is high/ low HDL/ altered LDL more In T2 patients- TGL is high/ low HDL/ altered LDL more

atherosclerosisatherosclerosis

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Non Diabetic causes for high blood sugar

Endocrinal- high steroids/ high GH/ glucagon tumorsEndocrinal- high steroids/ high GH/ glucagon tumors Drugs- niacin/ steroids/ diureticsDrugs- niacin/ steroids/ diuretics Liver diseaseLiver disease

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Diabetes Management

Clinical Trials Data:Clinical Trials Data: T1 patients:T1 patients: Tight glycemic controls reduce complications by 60% but Tight glycemic controls reduce complications by 60% but

increase the risk of therapy induced hypoglycemia three fold!increase the risk of therapy induced hypoglycemia three fold!

T2 patients: T2 patients: ‘impaired glucose/ “prediabetes” group- ‘impaired glucose/ “prediabetes” group- PREVENTION!: Low fat diet and 150 minutes of brisk walk/week PREVENTION!: Low fat diet and 150 minutes of brisk walk/week reduced progression to Dm by 71%. Preventive drug therapy reduced progression to Dm by 71%. Preventive drug therapy not usefulnot useful

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Kumamoto studyUKPDSstudy Steno-2 study

Data: Intensive treatment of T2 DM with drugs/ achieving Data: Intensive treatment of T2 DM with drugs/ achieving HgbA1c levels less than 7% with glypizide/ glyburide (HgbA1c levels less than 7% with glypizide/ glyburide (not not metformin or chlorpropamide)metformin or chlorpropamide) reduced diabetes related reduced diabetes related microvascular complications by 50%microvascular complications by 50%

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DM management

DietDiet DrugsDrugs InsulinInsulin Steps- Diagnosis/ Patient educationSteps- Diagnosis/ Patient education Acceptable levels of glycemic controlAcceptable levels of glycemic control Chronic Complications of DMChronic Complications of DM

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DIET

Determine calorie requirementsDetermine calorie requirements 45-65% from carbohydrate sources*45-65% from carbohydrate sources* 25-35% from fat (7% saturated)25-35% from fat (7% saturated) 10-35% from proteins10-35% from proteins

•*In T2 patients limit carbohydrates by *In T2 patients limit carbohydrates by substituting calories with mono-unsaturated substituting calories with mono-unsaturated fatty acids: olive oil/ rapeseed (canola)/ oils fatty acids: olive oil/ rapeseed (canola)/ oils in nuts or avocados. This will help to lower in nuts or avocados. This will help to lower TGL/ increase HDLTGL/ increase HDL

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Additional dietary caveats:

Limit cholesterol consumption to 200-300 mg/dayLimit cholesterol consumption to 200-300 mg/day Restrict protein intake to 10% of calorie requirements if there Restrict protein intake to 10% of calorie requirements if there

is renal failureis renal failure High soluble fiber dietHigh soluble fiber diet Artificial sweeteners only in limited usageArtificial sweeteners only in limited usage

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T2: Drugs for sugar control

1.1. Stimulate beta cells sulfonyl urea receptorsStimulate beta cells sulfonyl urea receptors2.2. Alter insulin actionAlter insulin action3.3. Affect dietary glucose absorptionAffect dietary glucose absorption4.4. Incretin mimetics or prolong incretin actionIncretin mimetics or prolong incretin action5.5. Glucagon suppressorsGlucagon suppressors

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# 1 -Stimulate beta cells # 1 -Stimulate beta cells

Second generation sulfonylureas-Second generation sulfonylureas-Glyburide (DiaGlyburide (Diaββeta)/ Glipizide (Glucotrol)eta)/ Glipizide (Glucotrol)

Glimeperide (Amaryl)Glimeperide (Amaryl) : Act for 12-24 hrs : Act for 12-24 hrs

Can cause prolonged hypoglycemiaCan cause prolonged hypoglycemia

Caution in hepatic impaired patientsCaution in hepatic impaired patients Repaglinide (Prandin)/ Nateglinide (Starlix):Repaglinide (Prandin)/ Nateglinide (Starlix):

stimulates insulin secretion, but less hypoglycemic stimulates insulin secretion, but less hypoglycemic

Induce weight gainInduce weight gain

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# 2 Drugs that alter insulin action

Biguanides- Biguanides- Metformin (Glucophage)Metformin (Glucophage) Reduces hepatic gluconeogenesisReduces hepatic gluconeogenesis Appetite suppressantAppetite suppressant GI upset- (20%) anorexia/nausea/vomiting/bloating/ GI upset- (20%) anorexia/nausea/vomiting/bloating/

diarrheadiarrhea Lactic acidosisLactic acidosis Does not cause hypoglycemiaDoes not cause hypoglycemia

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# 2 Drugs that alter insulin action

‘‘Glitazones’: Rosi (Avandia)/ Pio (Actos)Glitazones’: Rosi (Avandia)/ Pio (Actos) Alters the genetic expression of resistin (blocked) and adiponectin (stimulated) Alters the genetic expression of resistin (blocked) and adiponectin (stimulated)

from fat cells. from fat cells. Adiponectin normally increases insulinAdiponectin normally increases insulin sensitivitysensitivity of the tissues of the tissues Resistin normally causes insulin Resistin normally causes insulin resistanceresistance. Blocking it reduces insulin resistance. Blocking it reduces insulin resistance Decreases free fatty acids/ decreases hepatic glucose output. Does not cause Decreases free fatty acids/ decreases hepatic glucose output. Does not cause

hypoglycemiahypoglycemia BUT increase- total cholesterol/LDL/HDLBUT increase- total cholesterol/LDL/HDL AVANDIA increases risk of angina/MI AVANDIA increases risk of angina/MI not prescribed but ACTOS is ok.not prescribed but ACTOS is ok.

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# 3 Affect dietary glucose absorptionAffect dietary glucose absorption

Alpha glucosidase inhibitors- Alpha glucosidase inhibitors- Acarbose (Precose) / Miglitol (Glyset)Acarbose (Precose) / Miglitol (Glyset) Reduces postprandial hyperglycemiaReduces postprandial hyperglycemia Side effects – flatulence (30%)Side effects – flatulence (30%)

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Gila Monster Heloderma suspectum

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# 4 Incretins

Exenatide (Byetta)- GLP-1 receptor Exenatide (Byetta)- GLP-1 receptor agonist from the saliva of venomous agonist from the saliva of venomous lizard- Gila Monsterlizard- Gila Monster

Suppresses glucagon release and delays gastric emptyingSuppresses glucagon release and delays gastric emptying Helps to reduce HbA1c and lose weight – risks hypoglycemia and Helps to reduce HbA1c and lose weight – risks hypoglycemia and

pancreatitis, affects other drugs gastric emptyingpancreatitis, affects other drugs gastric emptying

Sitagliptin (Januvia) Sitagliptin (Januvia) (DPP-4= Di-Peptidyl-Peptidase-4 enzyme) inhibitor(DPP-4= Di-Peptidyl-Peptidase-4 enzyme) inhibitor

Improves HbA1c. No weight loss. Nasopharyngitis/URTIImproves HbA1c. No weight loss. Nasopharyngitis/URTI

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# 5 Other drugs

Pramlintide (Pramlintide (SymlinSymlin) analog of islet cell polypeptide amylin) analog of islet cell polypeptide amylin Delays gatric emptying, suppresses glucagon secretion and Delays gatric emptying, suppresses glucagon secretion and

decreases appetite. decreases appetite. Used in T1 and T2Used in T1 and T2

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# Insulin and T1/T2 Produced by rDNA technology ‘human’ insulinsProduced by rDNA technology ‘human’ insulins Action: Onset/Peak/DurationAction: Onset/Peak/Duration Rapidly acting-5’-15’/1-1.5hrs/3-4hrsRapidly acting-5’-15’/1-1.5hrs/3-4hrs Insulin lispro (Humalog), aspart (Novolog), glulisine (Apidra)Insulin lispro (Humalog), aspart (Novolog), glulisine (Apidra)

Short acting regular- 30-60’/2hrs/6-8hrsShort acting regular- 30-60’/2hrs/6-8hrs Intermediate acting- 2-4hrs/6-7hrs/10-20hrsIntermediate acting- 2-4hrs/6-7hrs/10-20hrs NPH insulinNPH insulin

‘‘Premixed’ NPH/Regular marketed as 70/30 or 50/50 or Premixed’ NPH/Regular marketed as 70/30 or 50/50 or 75/2575/25

Long-Acting glargine (Lantus)- 1.5hrs/falt/~24 hrsLong-Acting glargine (Lantus)- 1.5hrs/falt/~24 hrs detemir (Levemir)- 1 hr/ flat/17hrsdetemir (Levemir)- 1 hr/ flat/17hrs

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DM Issues

Watch out and recognize hypoglycemic features in patients Watch out and recognize hypoglycemic features in patients being treated with insulinbeing treated with insulin

Complications of DM that increase the risk of hypoglycemia- Complications of DM that increase the risk of hypoglycemia- autonomic neuropathy/ gastroparesis/ renal failureautonomic neuropathy/ gastroparesis/ renal failure

Lipodystrophy at injection siteLipodystrophy at injection site

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Chronic complications of DM

1.1. Ocular- Ocular- Cataracts/ Retinopathy/ GlaucomaCataracts/ Retinopathy/ Glaucoma

2.2. Renal- Renal- ESRD (T1>T2)/(good glycemic control and use of ACEi can reduce ESRD (T1>T2)/(good glycemic control and use of ACEi can reduce the development) Always check for proteinurithe development) Always check for proteinuri

3.3. Neuropathy-Neuropathy-Distal symmetrical ‘neuritis’- pain, touch, temp, vibration/ Distal symmetrical ‘neuritis’- pain, touch, temp, vibration/ claw toes-calluses and ulcers Charcot’s arhtropathy; burning pain claw toes-calluses and ulcers Charcot’s arhtropathy; burning pain (hypersensitivty)(hypersensitivty)Autonomic neuropathy/ EDAutonomic neuropathy/ ED

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Chronic complications of DM

44 Cardiovascular- Cardiovascular- heart failure-cardiomyopathy-IHD-metabolic heart failure-cardiomyopathy-IHD-metabolic syndrome-HTN-microvasculitis - peripheral vascular disease and syndrome-HTN-microvasculitis - peripheral vascular disease and gangrenegangrene

55 Skin and mucous membrane- Skin and mucous membrane- necrobiosis-candidiasisnecrobiosis-candidiasis

66 Pregnancy and DM- Pregnancy and DM- tight control with normal HbA1c critical to tight control with normal HbA1c critical to reduce spontaneous miscarriages-congenital malformations-reduce spontaneous miscarriages-congenital malformations-polyhydramnios-preterm labor-still birth-fetal macrosomia; risk of polyhydramnios-preterm labor-still birth-fetal macrosomia; risk of retinopathy/ preeclmapsiaretinopathy/ preeclmapsia

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HYPOGLCEMIA!

Fasting- insulinomas/ Addison’s/ myxedema/liver Fasting- insulinomas/ Addison’s/ myxedema/liver malfunction/malfunction/

Postprandial-Postprandial- Alcohol mediated- blocks conversion of glycogen to glucose in Alcohol mediated- blocks conversion of glycogen to glucose in

the liverthe liver Drug induced- Quinine/ Quinidine/ Quinolones (?)Drug induced- Quinine/ Quinidine/ Quinolones (?)

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Managing hypoglycemia

If blood glucose is 70 mg/dL or below: Eat or drink 15 g of carbohydrates# Recheck your blood glucose in 15

minutes. If the reading is not above 60 mg/dL.

Test again in 15 minutes If blood glucose is not > 70 mg/dL, repeat

treatment with another 15 g of carbohydrate, then call your health care provider

#The following contain 15 g of carbohydrate and are appropriate for the treatmentof hypoglycemia:

Glucose tablets (3, 5 g tablets) 4 oz of juice or soda (not diet) 1 tablespoon of table sugar or honey 1 small box of raisins Another useful formula that can help

patients emerge safely from hypoglycemia without spiking into a glycemic state:

(100 - blood glucose) X 0:2 = grams of carbohydrates

necessary for blood glucose correction Thus, if the blood glucose is 50 mg/dL, the

patient would consume 100–50 = 50; 50X 0.2 = 10 g of carbohydrates

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Useful Lab Tests in Diabetes Care

Biochemistry-Biochemistry- Urine Analysis- Urine Analysis- Protein/Sugar/KetonesProtein/Sugar/Ketones Look for microalbuminurea in patients Look for microalbuminurea in patients

with DM duration greater than 10 yrs. with DM duration greater than 10 yrs. Early sign of kidney involvementEarly sign of kidney involvement

FBS/PPBS/RBSFBS/PPBS/RBS HbA1c (~6% or less)HbA1c (~6% or less) Lipid profileLipid profile BUN & CreatinineBUN & Creatinine Red flags-Red flags- Sugars less than 50 Sugars less than 50 Sugars greater than 250 Sugars greater than 250

Others-Others- ECG/ Stress testECG/ Stress test Doppler vascular studiesDoppler vascular studies Ophthalmic studies for cataracts/ Ophthalmic studies for cataracts/

retinal issuesretinal issues FGIDs (functional gastro intestinal FGIDs (functional gastro intestinal

disorders)disorders)

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Diabetic Foot! Charcot!

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Diabetic Foot Care Visual inspection, palpation of the foot, vascular and neurologic

assessment, dermatologic assessment, motorexamination, and determination of range of motion of the foot and ankle.

Look for: 1. Healing injuries, bruising, or skin disturbances; bunions, hammertoes, a rocker

bottom foot, or Achilles contracture2. Vascular skin changes: stasis dermatitis, skin atrophy, hair loss, nail changes, or

clear areas of decreased perfusion; dryness, scaling, swelling, thickening of the tissues, and the temperature of the foot

3. Presence or absence of pedal pulses, and degree of sensory loss (neuropathy)4. Check the toe web spaces for evidence of tinea pedis, maceration,

fissures, or ulceration. Global erythema and swelling may represent Charcot changes or cellulitis

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Diabetic Foot Care

Neurologic status: (50% affected)Recent onset of pain, numbness, tingling, or other paresthesias?Subjective sensory tests, with comparison to the contralateral limb-Loss of the Achilles deep tendon reflex128-hz tuning fork

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Define neuropathy!

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Peripheral neuropathy- pain or loss of feeling in the toes, feet, legs, hands, and armspain or loss of feeling in the toes, feet, legs, hands, and arms

Proximal neuropathy (amyotrophy)- pain in the thighs, hips, or buttocks, leading to weakness in the legspain in the thighs, hips, or buttocks, leading to weakness in the legs

Focal neuropathy-dysfunction of one group or a group of nerves, resulting in muscle weakness dysfunction of one group or a group of nerves, resulting in muscle weakness or painor pain

Distal symmetrical polyneuropathy- ‘stocking-and-glove’ typemost common

Cranial neuropathy- acute-onset diplopia with ptosis and papillary sparing associated with an ipsilateral headache

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Risk factors for the development of diabetic Risk factors for the development of diabetic neuropathyneuropathy Modifiable Modifiable risk factors Obesity Hypertriglyeridemia Cigarette smoking Hypertension Elevated A1C Glycemic variability

NonmodifiableNonmodifiable risk factors Duration of diabetes Age Family history of neuropathic

disease

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Drugs used in treating neuropathy:

Antidepressants: Duloxetine/ Venlafaxine/ Tricyclics (TCAs) Anticonvulsants: Pregabalin/ Gabapentin/ Carbamazepine/

Lamotrigine/ Topiramate/ Opioids: Oxycodone CR/ Tramadol/ Topical agents: Capsaicin/ Lidocaine Patch Miscellaneous: Magnesium oxide