DIABETES MELLITUSSepehr Khashaei, MD

Overview• Prevalence increasing each year in US mainly due to

increase in obesity.• 4,000 cases diagnosed daily.• 7% of US population.• Highest incidence in American Indians• high incidence in Hispanics, Mexican Americans, and

African Americans.• Caucasians have the lowest rate in the world.• If you were born in 2000, your risk of developing any

kind of DM is 33% (males) and 39% (females).• Twice the death rate of non-diabetics from CAD.

Overview (continued)

• 200 amputations daily.• Life span is reduced by 12 years (males) and

19 years (females).• Treatment accounts for at least 14% of US

health care expenditure.

Type 1 DM• Insuficent amount of insulin.• Immune-mediated• 10% of patients with DM• Avoid using the terms IDDM or juvenile-onset

diabetes DM.• Sporadic (usually not hereditary).• Treated with insulin

Type 1 DM (continued)

• Patients prone to ketosis.• Associated with autoimmune diseases

especially: hypo/hyperthyroidism, adrenal insuficiency, celiac sprue, vitiligo, B12 deficiency, maysthenia gravis.

Type 1 DM treatment

• Use long-acting insulin such as NPH, glargine and detemir to cover the fasting and pre-meal states

AND

• Use short-acting insulin such as regular, lispro and aspart to cover meals.

Type 1 DM treatment (continued)

• Can also be treated with a continuous, subcutaneous insulin infusion done with a small pump that provides a continuous basal rate all day, with programmed increases prior to meals.

• Pumps carry a danger of hypoglycemia, and this may be fatal if it occurs at night or is otherwise unrecognized especially in someone with CAD.

GENERIC BRAND FORMRAPID ACTINGLispro Humalog AnalogAspart Novalog AnalogRegular Humulin R or Novolin R HumanINTERMEDIATENPH Humulin N or Novolin N HumanLONG ACTINGGlargine,Detemir Lantus,Levemir Analog

COMMONLY USED INSULINS IN THE U.S.

GENERIC BRAND FORMMIXTURES

70% NPH/30% regular

Humulin 70/30 or Novolin 70/30

Human

75% NPH/25% lispro

Humalog Mix 75/25Novolog

Analog

70% NPH/30% aspart

Novolog 70/30

Analog

TIME OF ACTION OF INSULINS

ONSET PEAK (hr) DURATION(hr)

Lispro, aspart

< 15 min 0.5-1.5 3-4

Regular 0.5-1 hr 2-3 3-6

NPH 2-4 hr 6-10 10-16

Glargine, detemir

2-4 hr Peakless (not)

18-24

Ultralente 6-10 hr 10-16 18-20

Insulin Pump

Dawn effect

• Increased blood glucose between 4 and 7 am• No preceding hypoglycemia• The cause is transient, mild, insulin resistance

due to the normal, early-morning rise in cortisol and GH.

Somogyi effect

• Hyperglycemia after immediate preceding hypoglycemia that theoretically stimulates the adrenal gland to release cortisol and temporarily increase blood glucose levels.

• Occurs any time of the day but calssically at night (with associated headaches and nightmare).

How to differentiate between Dawn phemomenon and Somogyi effect?• Check a 2am blood glucose:– If low = somogyi effect

• Treat Somogyi effect by decreasing evening insulin.

Type 2 DM• 90% of DM• Mechanism is insulin resistance• Strongly related to obesity (80% are obese).• Strongly hereditary• Avoid using the terms NIDDM or adult-onset

DM.• Usually treated initially with oral hypoglycemic

agents.• The age of onset has been decreasing.

DM type 2 (continued)

• More likely to get hyperosmolar nonketotic state than DKA.

Type 2 DM treatment• Diet and exercise and weight loss• Insulin• Oral hypoglycemic medication.• Injectable hypoglycemic medications• Insulin +/- hypoglycemic medication• Hypoglycemic medications

– Sulfanylureas – Glinides– Biguanides– Thizaolidinediones (TZD)– α- Glucosidase Inhibitors (AGI)– Amylin Analogs– Incretin Mimetics– Dipeptidyl-Peptidase 4 Inhibitors (DPP4I)

Sulfanylureas

• Increase insulin secretion from the pancreas.• 1st generation (acetohexamide, chlorpropamide,

tolazamide and tolbutamide• 2nd generation (glipizide, glyburide and

glimepiride)• 2nd generation drugs preferred over first

generation and less expensive.• Approved for use in combination with most

other drugs except glinides.

Sulfanylureas (continued)• Half-life is long• Fast acting (can titrate to maximal dose in 2-4 weeks).• Hypoglycemia can persist in states of overdose or

renal impairment.• Use with caution in elderly and in declining renal

function.• Severe hypoglycemia mandates an admission to the

hospital because of need for frequent monitoring and possible need for iv glucose therapy.

Glinides

• Repaglinide and nateglinide• Increase insulin secretion from the pancreas• Rapid-acting• Short half-life• Major effect is on postpranial glucose.

Biguanides• Metformin• Reduce hepatic glucose production and lowers

insulin resistance.• Used as the first line of treatment (even in

prediabetes) if no contraindications• Decreased mortality.• No weight gain (and possibly some weight loss)• No hypoglycemia when used alone• Decreases LDL and triglycerides.• Decrease risk of CAD (cardioprotective)

Biguanides (continued)• Side effect: dose-related abdominal pain and

diarrhea and propensity for causing lactic acidosis

• Contraindicated if creatinine ≥ 1.5 in a male or ≥ 1.4 in a female, decompensated or significant CHF, and acute or chronic metabolic acidosis, and hepatic insuficiency.

• Hold in acutely ill patients and in those scheduled for contrast procedures or surgery

Thiazolidinediones (TZD)• Rosiglitazone and pioglitazone (preferred)• Enhance insulin sensitivity• Very effective for reducing insulin resistance.• Take 6 wks to 3 months to take effect.• Extremely effective in treating NASH and POD• Modest reduction in blood pressure• Increase HDL and decrease triglycerides• Adverse effects: edema and weight gain.– Contraindicated in patients with class III or IV CHF

and CAD• Monitor the LFT’s periodically.

Amylin Analogue (pramlintide)• Amylin is a hormone secreted by pancreatic

beta cells along with insulin and helps to regulate influx by suppressing glucagon and slowing stomach emptying.

• Centrally mediates modulation of appetite decreasing food intake

• Used with insulin to lower post prandial blood sugars

• Also used in Type 1 DM• Given as SC injection

Incretin Mimetics (exenatide)• Enhance glucose dependent insulin secretion in

response to food• Has glucagon-like peptide-1 (GLP-1) activity• Suppresses glucagon• Delayed gastric emptying• Acts in brain to affect satiety (therefore helps with

losing weight)• GLP-1– Secreted from L cells in intestine– Most well characterized incretin– Decreased in Type 2 diabetes

Exenatide (continued) • Decreases plasma glucose acutely to near normal levels• Long duration in plasma after SC injection• Approved for use in patients with BG uncontrolled with metformin or

sulfonylureas.• Hypoglycemia not seen if used alone or with metformin.• > 85% lose weight.• Can lower lipids and blood pressure.• Requires injection in AM and PM.• Is expensive• Improves postpranial and fasting glucose.• D/c if pancreatitis. Don’t start if h/o pancreatitis.• Can cause renal failure. Do not use if GFR <30 or at high risk of acute

renal failure.• Major SE: nausea (tends to decrease with time). Start with lower

dose if nausea.• Reduce dose of sulfanylurea by 50% when adding this. Give for one

month and if glucose still high, increase sulfanylurea by 25%.

α- Glucosidase Inhibitors (AGI)

• Acarbose and miglitol• Delay carbohydrate absorption in the gut.• Biggest effect is on postpranial glucose.• Given three times a day with meals.• GI side effects (flatulence, abdominal bloating,

and diarrhea) makes them intolerable to a lot of patients.

Dipeptidyl-peptidase 4 inhibitors

• Sitagliptin• Slow the inactivation of natural incretins, such

as glucagon-like peptide 1 (thereby increasing their concentration).

• Biggest effect is on postpranial glucose.• Associated with weight loss.• Lower instances of hypoglycemia.

• Early institution of treatment of DM at a time when the A1C is not significantly elevated is associate with improved glycemic control over time and decreased long term complications.

• Long-acting insulin: Starting dose is typically at a 0.2 units per Kg per day, and titrated in increments of 2 units approximately every 3 days. Can titrate faster in hospitalized patients.

• Combination of oral agent with insulin is no better than adequate insulin alone.

• Consider starting the patient on insulin when HgbA1C >9.0

• Do not measure or treat lipids in a diabetic patient till BG is under control.

• Get Fasting blood glucose down first and then work on postpranial BG control.

Other causes of DM

• Pregnancy (Gestational)• Medication-Induced

E.g. niacin, steroids, thiazides, oral contraceptives, beta-blockers.

• Endocrinopathies (Cushing’s, acromegally)• Pancreatic defects and injury.

Impaired Fasting Glucose• Avoid using the term pre-diabetes• Diagnosed by:

1. Fasting plasma glucose 100-125 on two different occasions or

2. 2-hr plasma glucose of 140-199 after a 75-gm glucose load) on two different occasions or

3. One of number 1 & one of number 2.

Diagnosis of DM

1. Fasting (at least 8 hours) blood glucose ≥ 126 on two different occasions or

2. Random plasma glucose ≥ 200 on two different occasions with symptoms (polyuria, polydipsia, weight loss, fatigue), or

3. 2-hr plasma glucose ≥ 200 after a 75-gm glucose load (done after an 8 hour fast), or

4. Hemoglobin A1C ≥ 6.5 on two separate occasions.

5. Any combination of two of the 1-4.

Screening for DM

• Screen the following patients for DM annually beginning at age 30 (FPG preferred):– 1st degree relatives with DM– CAD– Acanthosis nigricans and BMI ≥ 25– Sedentary– Non-caucasion race– h/o impaired fasting glucose– HTN

Acanthosis Nigricans

Acanthosis Nigricans

Acanthosis Nigricans

Acanthosis Nigricans

• Acanthosis nigricans is common in younger patients and correlates with insulin resistance. In older patients, it suggests GI malignancy.

Screening (continued)

– Hyperlipidemia– H/o gestational diabetes– h/o delivery of > 9 lb infant– Polycystic ovarian disease– Pscyhiatric disease

• Without the risk factors mentioned, start screening at age 45 years.

Screening (continued)

• Important point: Finger sticks are acceptable for self monitoring on known DM, but only plasma/serum should be used for diagnosis. This is because whole blood (finger stick) glucose values are about 15% less than serum/plasma values.

Impaired fasting glucose

• 1/3 will develop Type 2 DM• 1/3 will normalize• 1/3 will stay as impaired fasting glucose• Still have risk for developing microvascular

disease.• Promote weight loss , regular exercise and low

sodium, high-fiber, low fat diet.

Impaired fasting glucose (continued)

• Consider metformin or acarbose in high-risk patients.

• Lipid, blood pressure goals, and aspirin therapy should be the same as for diabetes.

• Annual urine test for microalbuminuria and and annual fasting lipids.

• Twice yearly Hgb A1C.

Hgb A1C

• Check again in 6 months if no change in DM medications

• Check again in 3 months if any change in DM medications

• Goal is to keep Hgb A1C < 7 (great control)• 7-8 is considered fair control• 8-9 is considered moderate control• >9 is considered poor control

Long-Term Complications of IDDM

• Visual impairment 14%• Blindness 16%• Renal failure 22%• Stroke 10%• Amputation 12%• MI 21%• Median survival afterdiagnosis of IDDM (yr) 36

Other Therapies

• ASA• ACEI• BP control• Lipid control• Immunizations• Rx for neuropathic pain• Rx for gastroparesis• Rx for ED

Diabetic Foot Exam

Diabetic Foot Exam

Diabetic Foot Exam

Diabetic Foot Exam

Diabetic Foot Exam (Monofilament)

Diabetic Foot Exam (bedside doppler)

Diabetic Foot Chart

Diabetic Foot Ulcer

Patient advice for foot care

• Avoid going barefoot, even in the home.• Test water temperature before stepping into a bath. • Trim toe nails to shape of the toe; remove sharp

edges with a nail file. Do not cut cuticles.• Wash and check feet daily. • Shoes should be snug but not tight and

customized if feet are misshapen or have ulcers. • Socks should fit and be changed daily.

Hypoglycemia

• Daytime episodes – are recognized by autonomic symptoms

(sweating, nervousness, tremor and hunger)

• During sleep– may produce no symptoms or cause night sweats,

unpleasant dreams, and early-morning headache

• If hypoglycemia is not aborted by the countercurrent regulatory mechanisms or by ingestion of carbohydrate, CNS symptoms develop (confusion; abnormal behavior, loss of consciousness or convulsions)

• Hypoglycemia unawareness: – as diabetes progresses, particularly with the

development of neuropathy, epinephrine-induced symptoms may become blunted and lose their effectiveness as warning signals

Glucagon

DKA (diagnosis)

• Blood glucose >250 and• Arterial PH of 7.3 or less and• Moderate or severe ketonemia

Precipitating factors• Infection (most common pneumonia and

UTI)• Noncompliance with insulin therapy• ETOH or drug abuse• Silent MI• Stroke• Pancreatitis• Trauma• Drugs (corticosteroids, higher dose of

thiazide diuretics)

DKA (Laboratory findings)• Significantly elevated plasma

glucose• Wide anion gap metabolic• Plasma sodium – tends to be low

in the face of modest osmolar concentration because of the hyperglycemia that draws intracellular water into the plasma space

Plasma potassium – initial normal to high (due to the translocation of K out of the cells into the extracellular fluid).Plasma phosphate – typically in negative phosphate balance due to decreased phosphate intake and phosphaturia caused by the glycosuria-induced osmotic diuresis

Treatment of DKA

• Determine hydration status: start IVF 0.9% normal saline

• No insulin until potassium level back

• Insulin: +/- start with loading dose of 15-20U Reg insulin, then 0.1 U/kg/hr as iv infusion (if serum glucose level doesn’t fall by 50-70 mg/dL in the first hour, double insulin infusion)

When serum glucose < 250 mg/dl

change to 5% dextrose in 0.45 % saline at 100-200 mL/h with adequate insulin coverage (0.05 to 0.1 U/kg/h as iv infusion or 10U sc q 2h). Keep glucose at 150-200 until metabolic control is achieved

Potassium: if K < 3.3

hold insulin and give 40 mEq/h of KCL; when K > 5.5, don’t give KCL; when K is between 3.3 and 5.5, give 20 to 30 mEq of potassium in each liter of IVF

FAMOUS BELCH• F=Feet• A=Aspirin• M=microalbumin• O=ophthalmological exam• U=u/a• S=smoking• B=Blood pressure• E=Education• L=Lipids• C=Creatinine• H=HgbA1CThe letters in Bold should be done biannually and the

rest annually.