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DIABETES OVERVIEW AND UPDATE
Barb Bancroft, RN, MSN, PNPChicago IL
Historical highlights
• 2nd century A.D. Greek physician, Areteaus, noted that “Diabetes is a mysterious disease…{in which} the flesh and limbs melt into urine.”
• The term “diabetes” is from the word for ‘siphon’, and it describes the continuous flow of fluids and food in and out of the body that leaves him constantly thirsty, copiously voiding urine and severely emaciated.
Historically…the name had something to do with the kidney…
• Diabetes (Greek)— “to siphon”• Mellitus— “sweet” or “honeyed”• Insipidus—”tasteless”• (1674)“Taste thy patient’s urine, for if it be
sweet…” ---Dr. Thomas Willis Most diabetics lived 3-6 yearsNURSE!...
Back porch diagnosis and dipsticks
• Urine specimens on the back porch…flies, ants, or bees…meant sugar in the urine…
• It wasn’t thaaaat long ago that we “dipstick’d” the urine for sugar
What’s in a name? The evolution…
• “Sugar diabetes”• Juvenile Onset Diabetes Mellitus (JODM)• Adult Onset Diabetes Mellitus (AODM)• Insulin Dependent Diabetes Mellitus (IDDM)• Non-insulin Dependent Diabetes Mellitus (NIDDM)• Type I (Roman numeral used)• Type II (Roman numeral used)• Type 1 (Arabic number)• Type 2 (Arabic number)
And, it’s not thaaaaaat easy either…other types…
• Type 1A (autoimmune)• Type 1B (idiopathic)• LADA (latent autoimmune diabetes in adults)—also
referred to as Type 1.5 Consider this diagnosis in a “skinny, type 2 diabetic
that doesn’t respond well to oral drugs”—usually misdiagnosed)
• MODY (maturity onset diabetes of the young)• Still making insulin? Do a C-peptide level – less than 1
ng/ml (0.331 mmol/L) = no insulin; above 1 ng/ml = still making insulin
Definition• Chronic disorder of carbohydrate, fat and
protein metabolism characterized in its fully expressed clinical form by an absolute deficiency of insulin (Type 1 diabetes) or a relative insulin deficiency (Type 2 diabetes).
• Huh?
Definition• Type 1—pancreatic beta cell failure due to
autoimmune disease (NO or minimal insulin) (actually type 1A—most common)
• Type 2—insulin resistance AND pancreatic beta cell dysfunction (50% normal insulin secretion with dx; after 6 years w/ disease, drops to 25%; eventually zero…)
• PLUS…diabetes is a prothrombotic, proinflammatory, a proatherosclerotic and a proaccelerated proaging disease! So be PRO-active in DX and RX!
RISK FACTORS for DIABETES
• Who’s sitting in YOUR waiting room? • Primary care? • OB? • Geriatrics?• Pediatrics?• Who’s laying in that bed in the coronary care
unit? Stroke unit?
Who should be screened for diabetes?
• Family history of type 1 or type 2diabetes (first degree relative)THE FOLLOWING ARE RISKS FOR TYPE 2 DIABETES• Family history of early coronary heart disease • Undesirable lipid levels• Hypertension or being treated for hypertension• High risk race (black, Native American, Asian, Pacific Islander) and
Ethnic group (Hispanic)• Obesity • Impaired glucose tolerance/impaired fasting glucose—metabolic
syndrome, PCOS, gestational diabetes, baby weighing greater than 9 lbs.
• Physical inactivity• If none of the above, start screening at 45 yr/ every 3 yr
First question--family history?
• A family history of diabetes—for both type 1 and type 2
• Type 2—almost all cases have a parent or grandparent; identical twin concordance rate is 80%
• Type 1—50-90% don’t have a family history; identical twin concordance rate is 35-50%; 5% chance (one in twenty) if sibling has T1DM;
Type 1 diabetes--How many genes?
• In the past five years researchers have found dozens of genes with links to diabetes
• Approximately 50 genes for type 1—about half are genes that coordinate the HLA system that helps the body recognize self vs. non-self; explains why other autoimmune diseases are associated w/ T1DM
• Celiac disease and Hashimoto’s thyroiditis
Type 1 diabetes—how many genes?
• Other genes that have been found mediate the immune response to viruses (explains the viral hypothesis as a possible trigger)
Type 2 diabetes--how many genes?
• Approximately 38 genes for type 2• Genes that control the amount of insulin produced
by the beta cells— and whether or not the insulin produced can overcome the insulin resistance
Family history of early coronary artery disease
• What’s early?• 1st degree relative
Undesirable lipid levels
• HDL less than 35 mg/dl (0.91 mmol/L) • Triglycerides greater than 150 mg/dl (1.70
mmol/L)• Think diabetes or hypothyroidism with the
above lipid profile• Draw a FBS or HbA1C and a TSH
Reducing triglycerides
• Fish oil capsules (omega 3s) can also reduce the TG (1 gm/day lowers TG by 5-10%; statins (rosuvastatin/Crestor, specifically) by 30%; diet changes by 20%--increased fiber, decreased trans fats, reduce added sugars, limiting alcohol)
• Higher doses for high TG (platelet problems with higher doses)—4 gm/day
• New info—doesn’t protect against CAD for primary prevention
(Arch Intern Med 2012;172:686)
Hypertension—which comes first?• Persistent 135/80 warrants testing for DM)• 50-60% have both DM and HTN at diagnosis— “the
deadly duo”• In a diabetic patient, a systolic pressure of 130-139
mmHg with a diastolic pressure of 85-89 mmHg, although classified as “high normal”, warrants PROMPT treatment
• However, lowering the BP to less than 120/70 doesn’t appear to improve outcomes
High risk groups for type 2 DM• Indian (from India)(#1)• Asian (#2)• Black/brown• Hispanic• Pacific Islanders• Native American Indians• Dark skinned individuals have a higher risk of Type 2 diabetes• Could it have something to do with vitamin D?• Beta cells also have vitamin D receptors on their surface, and
people with vitamin D deficiency are at increased risk for type 2 (darker skin increased melanin—decreased vitamin D conversion)
Type 2 diabetes risk factors--weight
• 85% are overweight or obese• (however, 2/3 of all overweight people and 1/3 of
obese patients will never develop diabetes)
Let’s dispel a few “old” myths…#1
• Is a calorie just a calorie just a calorie? • OLD ANSWER? YES, of course…cut calories? Lose
weight…• NEW ANSWER? Not exactly…potatoes have been
found to pack on the pounds more than the same amount of calories in walnuts…
• What kind of potatoes? FRENCH FRIES…then chips, soda, red meat, mashed potatoes
• (N Engl J Med June 23, 2011)
Location, location, location
• Abdominal (visceral)--obesity and insulin resistance (fat in the liver and muscle is insulin resistant)
• It’s a new organ…it’s metabolically active• It produces inflammatory mediators such as
TNF-α, IL-6, C-reactive protein, and adiponectin
• Waist greater than 102 cm (40 inches) in males and 88 cm (35 inches) in females
• Actually your waist should be ½ your height
What is the best way to reduce belly fat? WALKING…
• Ladies…the bad news…• exercise not only reduces insulin resistance
it also jump starts weight loss…
Metabolic syndrome
• DEFINITION: A clustering of risk factors that, in the aggregate, sharply increase the risk of cardiovascular disease and diabetes
• By the time a diagnosis of diabetes is made, 70-90% of patients have metabolic syndrome, irrespective of ethnicity or the definition used
• Female to male ratio -- (2:1)• Weight or body mass index is a major risk factor;
5% of normal weight; 22% overweight, and 60% of obese individuals have the metabolic syndrome
NCEP--ATP III guidelines for metabolic syndrome
• Central obesity—waist size greater than 40.2 inches in men, 34.6 inches in women
• High TG (>150 mg/dL/1.7 mmol/L or greater) or being treated for high triglycerides
• Low HDL (less than 40 mg/dL/1.03 mmol/L in men, less than 50 mg/dL / 1.30 mmol/L in women)—or being treated for low HDL
• Hypertension (≥ 130/85 mm Hg) or being treated for HTN
• Fasting glucose ≥ 100 mg/dL/ 5.5 mmol/L or being treated for diabetes
• WHO guidelines add microalbuminuria (urinary albumin to creatinine ratio 30-300 mg/g.
Other risk factors for Type 2 diabetes—Gestational Diabetes
• Gestational diabetes—5-9% of pregnant women in U.S.; rates have increased 122% between 1989 and 2004
• Risk factors—obesity, advanced maternal age (over 40? 6x greater risk) FH of DM, history of GDM or abnormal glucose metabolism,, ethnicity—Indian and Pakistani women have a 4x greater risk; Middle Eastern and African American women have a 2x greater risk; Lower income—higher risk
Impaired glucose tolerance
• Baby weighing greater than 9 lbs. or a• Small for Gestational Age (SGA) babies
• Were YOU, as a baby, exposed to intrauterine hyperglycemia ?
Polycystic Ovary Syndrome (PCOS)
• First article published in 1922 by 2 French MDs entitled: “The Diabetes of Bearded Ladies…”
• Metabolic syndrome is 2-3 x higher in women with PCOS
• Type 2 diabetes is 10x higher in women with PCOS• Liver and muscle tissues are insulin resistant; ovary is
NOT; hyperinsulinemia triggers androgen production with hirsutism and decreased ovulation
• Metformin (Glucophage) increases insulin sensitivity, decreases hyperinsulinemia, decreases androgens, and improves ovulation
Abnormal beta cell function—increased risk of type 2 DM
• “Oh, I’m so hypoglycemic…”• ONLY if it’s a documented history of
hypoglycemia• Documented with an oral glucose tolerance
test• Beta cells are not functioning normally after
a glucose load, hence beta cell dysfunction• ~30- 70% risk of developing type 2 DM
Duodenal exclusion surgery?
• Is the cure for diabetes just a scalpel away? Not so fast…Many diabetic patients that have had gastric by-pass surgery that bypasses the duodenum and the upper small intestine have observed that their diabetes disappeared within weeks of the procedure—before any substantial weight loss. Postprandial hyperglycemia and the return of diabetes…
• Gut bacteria and obesity—firmacutes vs. bacteriodetes
The surgical treatment of obesity
• Roux-en-Y gastric bypass or biliopancreatic diversion surgery vs. standard medical therapy
• 2 year follow-up• Complete remission with gastric bypass 75%;
95% for biliopancreatic diversion, as compared with NO remission w/ medical therapy (Mingrone)
Surgical vs. medical?
• Intensive medical therapy vs. gastric bypass or sleeve gastrectomy
• After 1 year, the primary endpoint, a HBA1C of 6% or less, only 12% of medical therapy patients achieved this goal, 42% in gastric bypass achieved the goal, and 37% in the sleeve-gastrectomy group (Schauer)
• Interesting….more to come with surgery for type 2 diabetes
Age and type 2 diabetes
• The older you are, the higher the risk• Start screening at 45 and every 3 years
afterwards• 50% of all type 2 diabetics are over 60; • 18% are 65-75; • 40% of people over 80 have diabetes
Sedentary lifestyle
• Lifestyle (Lack of physical activity and sedentary lifestyle)
• GET OFF THE COUCH• GET OFF THE LAZY BOY• Move it, move it, move it
What does exercise do?
• Improvements in glucose tolerance due to an increase in insulin sensitivity independent of weight loss
• Increase glucose uptake; decrease hepatic glucose production
• Aerobic & resistance• Effect is 24 – 72 hours; no more than 2 consecutive days
w/out
• Prevention of T2DM• Sigal RJ et al. Diabetes Care 27:2518, 2004)
Secondary diabetes• Exocrine pancreatic disease—cystic fibrosis• A 60-year-old with newly diagnosed Type 1 DM
and weight loss? Think pancreatic cancer• Cushing’s disease or syndrome• Drugs—corticosteroids, L-dopa, sympathomimetics,
niacin, glucosamine, thiazide diuretics, HAART , beta blockers
• Atypical anti-psychotics--Weight gain= Clozapine (Clozaril)(biggest offender) and #2 is Olanzapine (Zyprexa); 10 weeks/10 pounds
• Risperidone w/ intermediate weight gain,
Do the statin drugs increase the risk of type 2 diabetes?
• Latest findings…yes, BUT the statins’ proven power to prevent heart attacks and strokes outweighs ANY potential increase in type 2 diabetes risk
• Study of postmenopausal women—6.4% not taking statins developed type 2 DM vs. 9.9% among statin users (over an 8 year period)
• Manson J. Harvard Medical School, 1/10/12
Type 1A diabetes
• Type 1A DM—primarily diagnosed in pre-teens or teenagers; onset prior to age 40 in the majority of patients;
• A Pediatrician with 2000 patients will have 3-6 children in the practice with Type 1 diabetes
• Caucasians greater than darker skinned individuals
• Sardinia #1, Finland #2, Sweden #3
Type 1A Diabetes• Associated with immune response genes and HLA-DR3 and
HLA-DR4 (99%; 53% with both; only 3% of people without T1A DM have both; also DQB1 (genetic background of Northern Europeans—Sardinia, Finland)
• Autoimmune attack against beta cells of pancreas (anti-glutamic acid decarboxylase antibodies—anti-GAD; ICA {islet cell antibodies}; IAA {Insulin autoantibodies})—months to years
• Present with 3 p’s + weight loss—polyuria, polydipsia, polyphagia
• Classic presentation is in a Caucasian, blue-eyed, blonde-haired kid named…
Autoimmune disease
• What triggers the autoimmune response in a genetically susceptible individual?
• The most likely culprit is one of the childhood viruses…cross reaction? Molecular mimicry?
• Coxsackie B? Measles? Influenza A or B?• Or?
Triggers of Type 1 diabetes…
• Type 1 diabetes has increased by 5% per year since the 1980s
• In addition to viruses…• 3 other suspects..
Too little sun—vitamin D deficiency
• Sunphobia• Sunscreen maniac moms• The overuse and abuse of sunscreen!!• Kids playing inside (the “thumb tribe”)• Pushes the immune system in the wrong direction—• Abnormal regulatory T cells?• 2 pathways—TH1 and TH2 • Taking the TH2 pathway increases the risk of allergies and
autoimmune disease?
Too little dirt
• The hygiene hypothesis— GUT bacteria and priming the immune system
• Germphobic (mysophobic) *moms• LET THEM EAT DIRT!• (*irrational fear of DIRT)
Too much cow’s milk…
• Decreased risk in babies who are breast fed• Increased risk in drinking cow’s milk early in
life—is there a protein in cow’s milk that triggers diabetes in genetically susceptible individuals?
• Large scale clinical trial called TRIGR, testing this hypothesis and is scheduled for completion in 2017
Other autoimmune diseases associated with Type 1 diabetes
• Celiac disease—(12.3% of T1DM kids in Denmark have celiac disease; 6.4% in US have both—growth problems, iron deficiency anemia)—younger the age at DX for DM the greater the risk for celiac (Diabetes Care 2006; 29:2452-2456)—share HLA-DQB1 with Type 1 DM
Autoimmune disease
• Thyroid disease (Hashimoto’s thyroiditis)—4.8% with T1DM and HT); clinical presentation; check their TSH
• Pernicious anemia– 2.6%—antibodies to intrinsic factor resulting in a B12 deficiency (may present with peripheral neuropathy in addition to anemia)
• May develop years later—always have a high index of suspicion
Digression on B12 deficiency…3 possible causes in patients with DM1) pernicious anemia (autoimmune) in type 1
diabetes2) metformin in type 2 diabetes3) use of PPIs in either type 1 or type 2 diabetes
• B12 deficiency can cause peripheral neuropathy which may be falsely attributed to the neuropathy of diabetes (check B12 levels and check MCV as B12 deficiency can also result in a macrocytic anemia)
Diagnosis of diabetes
• Glucose levels—fasting plasma glucose or oral glucose tolerance test
• Hemoglobin A1C (glycated hemoglobin or glycosylated hemoglobin)
Glucose levels
• FBG--Before 1997 the diagnosis of DM was defined as a fasting blood glucose level of 140 mg/dL (7.8 mmol/L) or more OR
• OGTT with a 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) w/ 75 Gm of oral glucose
• In 1997 the WHO and ADA lowered the dx threshhold to 126 mg/dL (7.0 mmole/L)—the level at which retinopathy becomes detectable
• The diagnosis is confirmed by repeat testing on a separate day
Glucose levels
• In symptomatic patients, a random plasma glucose level of 200 mg/dL (11.1 mmole/L)or more also establishes the diagnosis
• The OGTT identifies more patients w/DM but is more expensive, more complex and has lower reproducibility—used today for gestational DM
Impaired glucose tolerance/impaired fasting glucose
• Impaired glucose tolerance (as defined by an oral glucose tolerance test (OGTT)—2-hour plasma glucose level of 140-199 mg/dL (7.8 to 11.0 mmol/L)
• OR• Impaired fasting glucose—single blood draw
testing sugar at a specific moment in time (ADA)—100 to 125 mg/dL (5.6 mmol/L – 6.9 mmol/L)
• Impaired fasting glucose (WHO)—110 to 125 mg/dL (6.1 – 6.9 mmol/L)
Progression to diabetes
• Persons categorized as “impaired” by either of these definitions have approximately a 5-10% annualized risk of diabetes, a risk that is greater than a factor of 5 – 10 than persons with normal glucose tolerance or normal fasting glucose
• If you have both the risk is approximately 10 – 15%
Inzucchi SE. Diagnosis of diabetes. N Engl J Med 2012 (August 9); 367 (6):542-550)
Diagnosis of diabetes• Hemoglobin A1C—gold standard for measuring long-term
glycemic control—how does it work? RBC life span• Glucose binds irreversibly with hemoglobin over the lifespan of
the RBC (glycated hemoglobin) – over 2 to 3 months• Normal range is 4-6%• Diagnosis of diabetes with level greater than 6.5% (ADA, WHO)• Pre-diabetes—A1C range of 5.7 -- 6.4%• Identifies fewer patients w/ diabetes than FPG or OGTT• 1/3 of patients dx with FPG only; 1/3 with A1C only; last third
w/ both tests• Certain conditions interfere with A1C –SCA, CKD, EPO;
decreased RBC turnover
Notes on HbA1C
• TIGHT control in the Type 2 diabetic does NOT always lead to the best outcomes (ADVANCE and ACCORD studies—a HbA1C of ~7 are more feasible and provide better outcomes
What about the geriatric patient?
• Each patient case is individualized• Quality of life is the biggest concern• We usually think of long-term complications
of treating diabetes, but in the elderly there can be some significant short-term complications
The Geriatric patient• Blood sugar -- HbA1C in the 8-9% range is reasonable
in older patients unable to live independently; less than 7% with a significant higher incidence of functional decline & deaths (regardless of Tx type) (Yau, J Am Geri Soc 2012 July;60:1215)
• Too low? hypoglycemia can break a hip• However, hyperglycemia can lead to polyuria,
incontinence, bed-wetting with skin excoriation, decubitus ulcers, dehydration, weight loss, visual changes (diplopia)
• Excoriation, decubitus ulcers• Consider co-morbidities before aggressively treating—
8 years needed benefit of glycemic control in reducing microvascular complications (retinopathy, nephropathy)
Co-morbidities?• 2-3 years for benefit from BP and lipid control for
reducing macrovascular complications• However, starting a patient on a “statin” drug
also has short-term benefits• Statins will decrease short term mortality and
morbidity• Stabilize plaques and decrease inflammation
which in turn decreases the risk of a plaque rupture, thrombosis and an MI or Stroke
• Blood pressure? Hypotension can break a hip, but hypertension can increase the risk of stroke
What about kids?
• More liberal numbers for kids and developing brains who are more vulnerable to the effects of hypoglycemia and who may not be able to effectively recognize or speak about the symptoms of hypoglycemia
INSULIN and GLUCAGON
• Insulin is a growth hormone—stores fat and sugar and stimulates protein synthesis after the meal
• Produced by the beta cells of the pancreas• Too much insulin? WEIGHT GAIN• Glucagon is a catabolic hormone produced during
the fasting state; breaks down stored glycogen• Produced by the alpha cells of the pancreas• Too much? WEIGHT LOSS
Right after a meal (The postprandial state)
• The pancreatic beta cells produce insulin• Insulin binds to insulin receptors and
facilitates glucose entry into liver and muscle cells to be stored as glycogen (glycogenesis)
• Lipogenesis—insulin binds with insulin receptors and facilitates the entry of lipids into adipocytes
• Protein synthesis—insulin facilitates the transport of amino acids into muscle
• GROWTH (anabolic hormone)
The fasting state
• Between meals and overnight • The pancreatic alpha cells produce glucagon• Glucagon triggers glycogenolysis (breaks down
stored glucose in the liver) to maintain a steady state of blood glucose (LIVER)
• Lipolysis—breaks down fat tissue and forms free fatty acids
• Gluconeogenesis—turns proteins into sugar
Ketoacidosis (DKA) in Type 1 diabetes
• Diabetic ketoacidosis is a prolonged fasting state with an absolute deficiency of insulin;
• Glucagon is working overtime—glycogenolysis; lipolysis; and gluconeogenesis
• Increased counterregulatory activity—↑ cortisol, ↑ catecholamines, ↑ growth hormone=↑ BS
• All contribute to hyperglycemia and osmotic diuresis• fatty acid release (ketones in the urine—osmotic
diuresis)--ketoacidosis• A young girl presenting with alternating hypoglycemia
and DKA – consider an eating disorder
Diabetic ketoacidosis (DKA)
• One in four cases of Type 1 diabetes presents with DKA
• Blood sugar > 300 mg/dL (fruity breath odor)• Significant ketosis – urine acetoacetate
(ketones), blood hydroxybutyrate)• Acidosis (pH< 7.3 or HC03 < 15) (mild – 7.2 – 7.3; moderate 7.1 – 7.2; severe <
7.1 or less than 7.2 in a child less than 5)
DKA – presenting complaints
• Gastroenteritis—abdominal pain, vomiting but NO diarrhea
• Dehydration (usually 7-10%)—but excessive urine output! (tachycardia, hypotension)
• Respiratory distress—but no lung findings Kussmaul’s respirations (acidosis)(hyperventilation with slow, deep sighing breathing)
• Confusion, decreased reflexes, coma
DKA--monitoring
• Flow sheets for vital signs, labs, rates of insulin, fluids, dextrose
• CLOSE ATTENTION to detail• Neuro status—checks every hour• ICU for severe acidosis, altered LOC, < 5 yrs,
increased risk of cerebral edema
Treatmentn of DKA—it’s complicated
• Dehydration is your biggest concern initially (10-20 mL/kg for 1-2 hours)
• GIVE FLUIDS…what kind? NS; change to ½ or ¾ depending on clinical status
• CHECK ELECTROLYTES & pH• Add K+ if less than 5.5 and with urination; 20 mEq/L if 4.5 to
5.5; 40 mEq/L if less than 4.5• Regular insulin IV (0.1 U kg/hr)• Then what? Check electrolytes and pH (Blood gases every
hour)• Should bicarb be given? RARELY, if EVER
Pathophysiology of Type 2 DM
• Early in the disease—as the body becomes resistant to insulin, the beta cells in the pancreas must pump out more hormone to compensate; people with beta cells that can’t keep up with insulin resistance can’t move the glucose into the muscle, fat and liver cells
• Insulin resistance is characterized by a rise in postprandial blood sugars
• Hyperinsulinemia results.• What are the consequences of hyperinsulinemia?
Hyperinsulinemia results in…• Increased triglycerides and decreased HDLs• Triggers release of angiotensin 2 → aldosterone• Vasoconstriction and sodium and water retention—
hypertension• Stimulate fat storage (CHO to fats)• Prothrombotic (increased AT2)• Proinflammatory (increased AT2)• Triggers endothelial cell dysfunction-fancy way of
saying, deposits LDL cholesterol and triglycerides into the arterial walls
• YIKES!!
Type 2 diabetes• Metabolic derangements aren’t usually as severe as
Type 1• Few symptoms initially, 2 P’s (no polyphagia), weight
gain due to hyperinsulinemia• Other symptoms—fatigue, diplopia, nocturia
(nocturnal diarrhea)• Skin infections, vaginal yeast infections, poor wound
healing (BS >180 mg/dL or 9 mmol/l), neuropathy• “Silent” for a full decade in some individuals
Treatment: Lifestyle changes
• Must be a part of any intervention• Exercise 30 minutes daily if possible or every
other day for sure…• And, nutritional counseling with reduced
calorie diet (more later)
Drugs, drugs, drugs
• Primary -- targets for HbA1C – 6.5% to 7%• Secondary – fasting BG less than 120 mg/dL• Post-prandial – less than 140 mg/dL
Oral drugs--#1 for Type 2 diabetes
Oral Drugs—the #1 oral drug• Metformin (glucophage) does not have any direct
effect on insulin release from the pancreas—doesn’t require insulin to work
• Primary action: DECREASE hepatic glucose production; also, decreases glucose absorption via the GI tract, and may increase sensitivity of insulin receptors
• Problem? GI blues (titrate slowly; nighttime dosing/give with food), need functioning organs--kidneys and heart especially (check serum creatinine before starting metformin)
• Se Creatinine--Cut-off is 1.4 (50-90 mmol/L) in females and 1.5 (70-120 mmol/L) in males;
Metformin (Glucophage)• Other benefits: lowers BP, increases HDL, lowers
LDL; • has been shown to be safe during PG (? Use for
gestational diabetes?)(N Engl J Med May 8, 2008)• Improvement in menstrual irregularities and
hirsutism (PCOS)--fertility• Metformin and breast cancer reduction (54%)—
Diabetes Care December 2010• Metformin and slowing the aging process• B12 deficiency may occur• Rare, rare, rare, for lactic acidosis
Oral drugs for type 2 DM…• 2nd tier: The “Glitazone” sister— pioglitazone (Actos)
(troglitazone/Rezulin and rosiglitazone/Avandia are history)—black box warning for bladder cancer with Actos
• Alter muscle and adipocyte metabolism to improve sensitivity to insulin with secondary effects in the liver
• May prolong beta cell function• Problem? Volume expansion, heart failure, dilutional
anemia, weight gain (peripheral, not central; may exacerbate macular edema)
• Good news? Reduce triglycerides; reduce fatty liver
OLD Drugs…effective, safe, and cheap drugs
• Oral sulfonylureas—Glipizide (Glucotrol) and glyburide (Diabeta, Micronase, Glynase) (used for gestational diabetes)and glimipiride (Amaryl)…
• Increase the secretion of insulin from the pancreas and increase receptor sensitivity; ? Promote beta cell failure??
• Problem? Weight gain, hypoglycemia• glimipiride (Amaryl)—safe use in elderly--decreased
incidence of hypoglycemia
Oral drugs before a meal
• Repaglinide (Prandin)*• Nateglinide (Starlix)• prevent postprandial excursions• Great if your meals are sporadic• Prandin* (better than Starlix)
The “gliptins”
• Weight neutral• Sitagliptan (Januvia) inhibits enzymes in the
intestine responsible for breaking down incretins; incretins potentiate insulin release
• Saxagliptin (Onglyza)• Linagliptin (Tradjenta)
Better…drug combinations
• Actosplus Met (metformin/pioglitazone)• Metaglip (glipizide and metformin)• Glucovance (glyburide and metformin)• Duetact (pioglitazone HCl and glimepiride)• Janumet (sitagliptan and metformin)• Kombiglyze (onglyza + metformin)
Incretin mimetics (April 28, 2005)—
• What are incretins? Incretins are responsible for approx. 60% of the post-meal insulin secretion, but the action of the incretins is impaired in diabetics)
• Exenatide (Byetta and Bydureon)—isolated from saliva of a Gila Monster
• Generally added on to Type 2 diabetics who are already receiving metformin, a sulfonylurea, or both and do not have optimal control
• Acts at the GLP-1 receptor, promoting insulin release• Weight loss is a + side effect (due to slowing of gastric
emptying and “feeling full”)• 2nd generation—liraglutide (Victoza)
The new face of Victoza
• Liraglutide (Victoza)…qd• Bydureon (Byetta once a week)• Better than Byetta as it reduces HgA1C 1.6%
vs. 0.9% for Byetta• Weight loss greater than Byetta but less than
liraglutide • Bydureon nausea 14% vs. Byetta at 35%
“Hi YA’LL…”—my name is Paula Deen
• The WEEK magazine had a contest…after she was diagnosed with type 2 diabetes they asked the readers to come up with the name of her new restaurant
• What was the winning name?
The discovery of insulin (“pancreatic extract”)
• Frederick Banting and his assistant, Charles Best experimented on diabetic dogs over the summer of 1921, and finally, dog number 92, a collie, hopped off the table after an injection and wagged her tail—this was the breakthrough
• In the spring of 1922, Elizabeth Hughes, age 11, daughter of Justice Charles Evans Hughes, traveled to Toronto to receive insulin; she weighed 49 pounds when she arrived
• Shortly after starting insulin she weighed 60 pounds• She lived another 60 years—By the time she died in
1981, at age 74, she had received 42,000 insulin shots
Insulin
• Prior to the discovery of insulin, diabetic children rarely survived more than 3 years
• The first child to use insulin in the U.S. was the son of an executive for Eastman Kodak—his insulin was smuggled across the Canadian/U.S. border
Eli J. Lilly and Company (Indianapolis)
• Won the right to mass produce insulin• First partnership negotiated among academia,
individual physicians and the pharmaceutical industry
• Chicago played a major role—slaughterhouses began sending trainloads of frozen porcine (pig) and bovine (cow) pancreas’ to Lilly’s plant in Indianapolis.
• By 1932 insulin’s price had fallen by 90 percent
Insulin• Insulin is the number one choice for type 1
diabetes due to the absolute deficiency of this hormone when diagnosed
• However, the pancreas will eventually give out in patients with T2DM and the oral agents will no longer work; over the course of 15 years, the proportion of patients using oral agents alone declines from 65% to 25%, with a corresponding increase in those using insulin
• BUT new studies show that insulin should be started EARLIER in Type 2 DM…better glucose control than w/ oral meds
Insulins
• Old “down –on-the-farm” insulins• Anything with the last name “ine”—bovine, porcine • Rapid-acting insulins include aspart (Novolog), glulisine
(Apidra), lyspro (Humalog),• Regular insulin—Novolin R and Humulin -R• Intermediate acting insulin—neutral protamine Hagedorn
(NPH)—Humulin N, Novolin N• Long-acting insulins include detemir (Levemir), glargine
(Lantus)
Starting a patient on insulin
• Blood sugar diary—blood sugar readings at different times of the day—fasting, before meals, two-hour postprandial, and bedtime to isolate when non-goal blood sugars are occurring
• Are they having trouble with the early morning rise in glucose, the “dawn” phenomenon?
NPH continues to have some usefulness
• Used to cover the DAWN phenomenon in patients – either type 1 or type 2; some type 2 patients have normal BS all day with oral agents, but their early morning rise isn’t controlled; NPH at 10 – 11 p.m. to maximize its glucose-lowering effects in the ddawn hours (~3 to 8 a.m.) when there is a natural increase in the “counter-regulatory” hormones—cortisol, GH, glucagon)
• Don’t use it too early—ie. At bedtime or early evening, as this will increase the risk for nocturnal hypoglycemia
Daily basal insulins• LANTUS (insulin glargine) or LEVEMIR (insulin detemir)—long-
acting basal insulins; they don’t have a peak; provide constant levels over 24 hours;
• If the blood sugars are mild to moderately high “around the clock,” the addition of a daily basal insulin is indicated
• How do you switch from NPH to Lantus? Easy• Can you mix other types of insulin with Lantus? NO• Does Lantus “look” funny? YES, compared to NPH, it’s clear• Lantus and Levemir stabilize endothelial cells…HUH? Reduce
atherosclerosis risk
Before we get to the complications of diabetes
• First of all, not all complications are inevitable• Better control, and a better understanding of
the disease process decreases “inevitable” complications
• The death rate from diabetes has been DECREASING even though the numbers are increasing
• SO, somebody out there is listening!!!
Complications of type 2 diabetes• Since we KNOW what the complications can be, let’s
start working on prevention as soon as the disease is diagnosed
• Accelerated atherosclerosis• Coronary artery disease, cerebrovascular disease,
peripheral vascular disease—diffuse disease; triple vessel CAD
• 10x greater risk of CHF in females with diabetes and a 6x greater risk of CHF in males with diabetes
• Risk of stroke is 2.5-4x greater in diabetics
Peripheral arterial disease
• Atherosclerosis of the aorta, iliac arteries, femoral arteries
• Intermittent claudication• Risk of amputation is 15-40 x higher in the diabetic• A diabetic foot ulcer precedes amputation 85% of
the time• Let’s hear it for WOCNs!• FOOT CARE!!
Wound care: What do they do with all of that circumcised foreskin?
• Apligraf• Regranex (PDGF)• How about honey for wounds??
Are they on aspirin and/or Plavix (clopidogrel)?
• Diabetes is a pro-inflammatory disease!• Diabetes is a pro-thrombotic disease• ASA is not for men under 50 and women under 60 UNLESS… other risk factors (smoking, HTN, high LDL) are present• Plavix if allergic to ASA• Plavix after a coronary event or cerebral event • Plavix with a stent• Diabetes Care , June 2010
Are they on a “Statin” to improve LDL cholesterol levels?? And to decrease inflammation?
• If not, why not?• LDL-levels should be reduced to 70 mg/dL• Say yes to the “statin” sisters—lova (Mevacor), atorva
(Lipitor), prava (Pravachol), simva (Zocor), fluva (Lescol), rosuva (Crestor), pitavastatin (Livalo)
• Statins are anti-inflammatory, anti-lipid, decrease plaque formation, stabilize plaques and prevent plaque rupture
• HDL greater than 40 mg/dL in men, greater than 50 in women
• Statins may also slow the progression of chronic renal disease (Fried)
Statin drugs• Should all diabetics be on statins REGARDLESS of their
LDL level? • YES…YES…YES…their anti-inflammatory effects are
even more beneficial; and even if their LDL level is normal, their LDLs tend to be small and dense (Pattern B—think BBs floating around in the arteries); statins may change the size of LDLs to large and LOOSE (Pattern A)!
• Small dense LDLs are even more damaging to artery walls
• The reason their LDLs are small and dense is because their triglycerides are too high--PAY ATTENTION to TG!!
• Fibric acid derivatives (fenofibrate) lower TG and increase particle size; extended release niacin also increases particle size
FYI
• Particle size and particle number can be determined by the NMR (nuclear magnetic resonance) LipoProfile—cost ~ $100 to $120, slightly higher than a lipid profile
• Many insurance companies cover the cost of NMR, including Medicare
• Goal for particle number is less than 1000 nmil/L and goal for LDL size is 20.6 nm or greater
What’s not to love about the statins? Yeah, yeah…side effects
• Myalgias **(other causes in elderly patients…)• Myositis; rhabdomyolysis (rare)(0.46 per 1 billion
prescriptions for DEATH from rhabdomyolysis)• About 1/20 patients experiences muscle pain or
weakness• Reduce the dose, don’t stop the drug• Change to Crestor? Give the statin every other
day?• Check the creatine kinase if muscle aches and
pains are severe
Dental care and diabetes
• 1 to 2 periodontal treatments per year decreased diabetes costs by 11-12%
• Univ of Michigan School of Public Health• January 8, 2009, Science Daily• Neuropathy and dry mouth• Increased risk of yeast infections• The cardiovascular/dental health connection
has been questioned
Hypertension and the diabetic
• 50-60% of all newly diagnosed diabetics have hypertension
• VIGOROUSLY treat hypertension to reduce the cardiovascular risks and to reduce the risk of nephropathy
• What drugs should be chosen for the treatment of hypertension? (Usually 2 are needed) First line therapy should be either the…
Prils or ARBs• Captopril (Capoten)• Enalapril (Vasotec)• Lisinopril (Prinivil, Zestril)• Perindopril (Aceon)• Moxepril (Univasc)• Benazepril (Lotensin)• Quinapril (Accupril)• Trandolapril (Mavik)• Ramipril (Altace)
• DO NOT USE DURING PREGNANCY!!
• losartan—Cozaar• valsartan—Diovan• candesartan—Atacand• irbesartan—Avapro• telmisartan—Micardis• olmesartan—Benicar• Eprosartan—Tevetan• Azilsartan--Edarbi
What should the 2nd anti-hypertensive drug be?
• Thiazide diuretic? (may increase BS)• Beta-blocker if they have tachycardia, angina
or previous MI (may mask symptoms of hypoglycemia)
• Calcium Channel blocker—verapamil or diltiazem for renoprotection
• Amlodipine (Norvasc)—another calcium channel blocker
Diabetic nephropathy• Nearly 24 million people in the U.S. have
diabetes; 180,000 are living with kidney failure as a result of diabetes
• Approximately 3% of newly diagnosed patients with type 2 diabetes have overt nephropathy
• In patients with type 1 diabetes, the development of nephropathy usually begins after 5 years of diabetes duration, with an increasing incidence of nephropathy over the next decade of duration to a peak at about 15 to 17 years of having had diabetes
The GOOD news…
• For people who live with diabetes for more than 25 years without any signs of kidney failure, the risk of ever developing it decreases
ANOTHER WAY TO PUT IT…• Patients who have no proteinuria after 20-25
years have a risk of developing overt renal disease of approximately 1% per year
The Bad News…
• Kids diagnosed with TYPE 2 diabetes have a 4 fold increased risk of renal failure vs. youth with TYPE 1 diabetes
• Kids with TYPE 2 diabetes have a 23-fold increase of renal failure and a 39-fold risk of dialysis compared to kids without DM
• Dart A. Diabetes Care, June 2012;35(6):1265-1271
Diabetic nephropathy…PREVENTION!!
• Treat high blood pressure!• Reduce the animal protein in the diet! Especially
if they have any evidence of renal involvement—the amino acids valine and lysine from animal meat increase intraglomerular hypertension and accelerate kidney damage
• Reduce serum glucose!• SAY YES to the ACE inhibitors or ARBs—the PRILS
or SARTANS (something to inhibit Angie and Al (Angiotensin and Aldosterone)
Treatment of Diabetic Nephropathy
• Intensive target-driven treatment with targets of: < 6.5% HbA1C, total serum cholesterol of <175 mg/dL, and a normal blood pressure
• Behavior modification program with diet and exercise, aspirin, and ACE inhibitors or ARBs
• All-cause death decreased vs. placebo group (30% vs. 50%)
• Decreased CV death, CV events, neuropathy, nephropathy, and retinopathy
(Goede P et al. N Engl J Med 2008 Feb;358:580)
A quick look at the functioning unit of the kidney…Blood supply to and from the glomerulus
• Afferent arteriole delivers blood to the• Glomerulus—a tuft of capillaries• Blood exits via the efferent arteriole
Barb’s artwork: the healthy kidney…
• Afferent arteriole (vasodilated via (prostaglandins)• Blood entering glomerulus
• Glomerulus→filter
• Efferent arteriole (vasoconstricted via (angiotensin 2)• Blood exiting glomerulus
PG
AT2 Toilet
filter
The Diabetic Kidney…insulin resistance, hyperglycemia, hypertension, animal protein
• Afferent arteriole ( vasodilation by ( prostaglandins)• Blood entering glomerulus
• Glomerulus→filter• Efferent arteriole ( vasoconstriction via ( angiotensin 2)• Blood exiting glomerulus**CVD and microalbuminuria
Microalbuminuria**
Microalbuminuria
• Indicates a stage of early nephropathy• Greater than 30 mg/day or,• Greater than 20 μg/min, or• an albumin to creatinine ratio of 30-300
μg/mg creatinine• Confirmed when 2 out of 3 tests are positive
in a 3 month period
Boosting HDLs to protect the kidney
• ** Higher HDLs--for every 21-mg/dL increase in HDLs, people are ½ as likely to develop albuminuria (Diabetes Care January 06)
• Say yes to STATINS• OUCH…• Interesting side effects of statins in women • “I never had diabetes, now I have diabetes…”
Digression on the diabetic diet…
• Diabetic Diet—circa 1917• “Forty-eight hours after admission to the hospital the
patient is kept on ordinary diet to determine the severity of his diabetes. Then he is starved, and no food allowed save whiskey and black coffee. Whiskey is given in the coffee: one ounce of whiskey every two hours, from 7 a.m. until 7 p.m. This furnishes roughly about 800 calories. The whiskey is not an essential part of the treatment: it merely furnishes a few calories and keeps the patient more comfortable while he is being starved.” (Starvation Treatment for Diabetes—1917)
Other diets
• Exchange diet• Counting carbs diet• Glycemic index diet• Mediterranean diet• The ALL YOU CAN EAT diet
The Cardiologist’s diet?
• “If it tastes good, spit it out!”
• The Old Country Buffet Diet
In addition to reducing animal protein, is there such a thing as a “diabetic diet”?
• Low calorie (PORTION CONTROL)• Low-fat (especially trans and saturated fats)• Low protein (especially ANIMAL protein to protect the
kidneys)• High fiber (20-35 grams per day)• Carbohydrates—what type? Count those carbs!• One visit to a nutritionist can save $13,872 per person
over a 4 year period; savings in hospital charges…one visit makes a HUGE difference
What about the Atkin’s diet to lose weight? NOOOOOOOO
• The Atkin’s diet is PRO-inflammatory• Saturated and trans fats• Increases intraglomerular hypertension
Know how to estimate portion size…
• One teaspoon of peanut butter is the size of your thumb’s first joint
• Roll the dice…cheese portion• Think baseball or tennis ball size for a portion of fruit
or pasta• Think deck of cards or palm of your hand (sans
fingers) for a portion of meat, fish, or chicken• Dove soap bar or mouse for the size of a baked
potato
Burning calories to lose weight…
• Besides the obvious activities for burning calories—walking, biking, hiking, swimming…
• The “little” things mean a lot too…
When you’re just about ready to take a bite..
• It takes 2 hours and one minute for a 130-pound person to walk off the calories in a McDonald’s BIG MAC;
• 3 hours and 26 minutes to walk off a Burger King Double Whopper, with cheese
Burn more calories than you take in…
• Stand up when talking on the phone…burn an extra 15 calories
• Chewing gum…burn an extra 11 calories• Tighten your rear-end when walking through a
doorframe…15 extra calories per squeeze• FIDGET
Burning calories
• Kiss your honey every a.m. burns 6-12 calories depending on the intensity of the kiss
Burning calories…
• A wild ride in the hay burns 125 to 300 calories depending on how wild that ride happens to be!
• New partner or “same old same old”…??
Helpful hints for burning calories..
• Passionate kiss three times a day… +• Mad, passionate love twice a week… =• 32,000 calories per year, the equivalent of a 9-
pound weight loss
OR...
• Banging your head against the steps for one hour burns 150 calories…this is a suggested alternative when a wild ride in the hay isn’t an option.
Diabetic peripheral neuropathy (DPN)—FOOT CARE
• Monofilament screening for sensory loss at every office visit
• Longest nerves first• Small fiber loss resulting in the loss of pain, light
touch, and temperature sensation• Large fiber loss later—loss of vibration and
proprioception• Stocking-glove distribution
Diabetic peripheral neuropathy— “Now where did I put that sewing needle?”
• Tingling or burning• Walking on hot coals• Walking on shards of glass—lancinating/shooting pains• Treatment—analgesics, antidepressants • Amitriptyline/Elavil, • (duloxetine/Cymbalta), • anticonvulsants (pregabalin/Lyrica) or
(gabapentin/Neurontin) • Opioids as necessary• Acupuncture, TENS, magnets (but not with an insulin
PUMP)
Autonomic neuropathy
• Evaluated and followed by a cardiologist• Orthostatic hypotension (also common w/ aging)• Resting tachycardia is an important sign of the LOSS
of vagal input• Silent ischemia and congestive heart failure• Need a beta-blocker (atenolol {Tenormin)• metoprolol {Lopressor, Toprol XL}),
bisoprolol/Monocor/Zebeta• Metoprolol or carvedilol (Lopressor or Coreg) with
CHF
Autonomic neuropathy
• Gastroparesis (wide swings in blood sugar with slowed digestion interfering with the timing of insulin), early satiety, chronic N & vomiting of food digested hours before
• Metoclopramide (Reglan, Maxeran), erythromycin, cisapride (special use), domperidone (Motilium)(Canada only)
• Gastric pacer
Erectile dysfunction
• Atherosclerosis and neuropathy are the 2 major causes
• ED is an accurate indicator of CVD• The Pfizer riser (and relatives—Levitra and
Cialis) are effective treatments in 50% of the cases
• Injections, implants, and suction devices • VED not TED
Autonomic neuropathy
• Impaired bladder emptying with hydroureter, hydronephrosis, chronic infection
• Urecholine, DuVoid
Diabetic Retinopathy—number 1 cause of blindness in U.S.
• SEE the EYE GUY once a year!
And lastly…TREAT the DEPRESSION!
Bibliography• Bloomgarden ZT, Comi RJ, Kendall DM. New therapies to achieve
glycemic control and weight loss in T2DM. Patient Care 2006 (February): 46-53.
• Fogel N, Zimmerman D. Management of Diabetic Ketoacidosis in the ED. Clinical Pediatric Emergency Medicine 2009; 10(4).
• Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int 2001;59:260-9.
• Feudtner C. Bittersweet: Diabetes, Insulin, and the Transformation of Illness. (Chapel Hill: The University of North Carolina Press, 2003)
• Gebel E. The other diabetes. Diabetes Forecast 2010 May:46-48.• Gondeck K. LDL particle number and size. ADVANCE for NPs and
PAs. January 2012• Migrone G, et al. Bariatric surgery vs. intensive medical therapy in
obese patients with diabetes. N Engl J Med 2012; 366:1577-85.
Bibliography• Nestler JF. Metformin for the treatment of polycystic ovary
syndrome. N Engl J Med 2008 Jan 3; 358:47-54• Nissen SE and Wolski K. Effect of rosiglitazone on the risk of
myocardial infarction and death from cardiovascular causes. N Engl J Med 2007 Jun 14; 356:2457-71.
• Psaty BM and Furber CD. Rosiglitazone and cardiovascular risk. N Engl J Med 2007 Jun 14; 356:2522-4.
• Ribowsky J. Gestational Diabetes. ADVANCE for NPs & PAs; November 2010; 31-48.
• Shah AA, Durso SC. Applying clinical practice guidelines in caring for older adults with diabetes. Patient Care 2007 (February): 18-25.
• Is Avandia a flawed drug or was the big new study flawed? Prescriber’s Letter 2007 (July).
Bibliography• Insulin glulisine (Apidra): A New Rapid-Acting Insulin. The
Medical Letter 2006; 48(1233).• Sitagliptin (Januvia) for Type 2 Diabetes. The Medical Letter
2007; 49(1251).• Sitagliptin/Metformin (Janumet) for Type 2 Diabetes. The
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Mellitus. Clinical News 2006 (December supplement).• Gavi S, Hensley J. Diagnosis and management of type 2
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• Vasconcelos A. Could surgery spell the end of diabetes? New Scientist, Sept 2007
LADA (Latent autoimmune diabetes in adults)—10% of all diabetics
• Typical age of onset – adult• Progression to insulin dependence – months to years• Presence of autoantibodies—yes• Insulin dependence – within 6 years• Insulin resistance – someThe presence of autoantibodies distinguishes this type
from type 2 and no need for insulin within the first six months distinguishes it from type 1.
Consider this diagnosis in a “skinny, type 2 diabetic that doesn’t respond well to oral drugs”—usually misdiagnosed
MODY—1 to 5% of all diabetics• Maturity-onset diabetes of the young• Monogenic (single gene abnormality)—the pancreas
cannot make enough insulin and/ or a defect in insulin secretion; autosomal dominant
• Usually diagnosed before age 25• 6 different subtypes—some don’t require insulin and
can be treated with oral medications• doesn’t progress to ketoacidosis; persistent
hyperglycemia; continued partial insulin secretion with no insulin resistance; mild to moderate hyperglycemia with a range of 130 – 250 (7 -14 mmol); absence of ++ antibodies or other autoimmune diseases
Intrauterine hyperglycemia and future risk of Type 2 DM or prediabetes
1) offspring of women with diet-treated gestational DM (21% of offspring develop T2DM or prediabetes )
2) offspring of genetically predisposed women with a normal OGTT (12% develop T2DM or prediabetes)
3) Offspring of women with T1DM (11% develop T2 DM or prediabetes)
4) Offspring of women from the normal population (4% develop T2DM or prediabetes)
(Diabetes Care 2008 Feb 01: 31(2):340-6)
Estimated average glucose—a calculated conversion of A1c
• eAG = 28.7 x A1c – 46.7
• A1c (%) eAG (mg/dL) 5.5 97 6 126 (7 mmol) 7 154 8 183 9 212 (11 mmol) 10 240 11 269 12 298eAG is a running average over the past 3 months of all glucose fluctuations;
used to help patients correlate their numbers with A1c.
Symlin (Pramlinitide)• Amylinomimetic agent for type 1 and type 2 diabetes—
synthetic analogue of the hormone amylin, which is deficient in patients with diabetes
• Acts by slowing gastric emptying, curbing appetite, and suppressing postprandial plasma glucagon and hepatic glucose output
• Adjunct therapy for patients with T1DM and T2DM who use mealtime insulin and have not maintained glycemic control despite optimal insulin therapy with or without oral drugs; cut mealtime doses by 50% with Symlin
• Improves postprandial blood glucose and promotes weight loss
