1、Ambulatory: Diabetes Mellitus,April 9, 2007,Insulin dependent (Type 1 /IDDM) Abrupt onset, 30 yrs Obesity Insulin resistance Impaired insulin secretion (beta cell dysfunction),Subtypes,Type I DM,Insulin deficiency secondary to -cell destruction usually by autoimmune process Insulin and C-peptide lev
2、els low May have islet cell autoantibodies, Autoantibodies to insulin, or antibodies to glutamic acid decarboxylase or tyrosine phosphatases. 20% risk of other autoimmune diseases Typically will present with DKA due to absolute lack of insulin,Type II,Insulin resistance and relative insulin deficien
3、cy - -cell mass preserved, but decreased secretion and response to insulin. Strong genetic component with 100% concordance in monozygotic twins. Ketoacidosis is rare though it can occur if concurrent infection. Also there are a small group of mainly African American patients in whom insulinopenia le
4、ads to a tendency to DKA. Usually hyperglycemia in Type II develops gradually and pt may be undiagnosed for years.,Subtypes,Gestational Diabetes Dysfunction of glucose metabolism with presentation in pregnancy Increased fetal morbidity Up to 63% will develop non-gestational DM in 5-16 years MODY (ma
5、turity-onset diabetes of the young) Subset of Type 2 DM Family history, early age of onset (teens, 20s) At least 5 subtypes Impairment of -cell function Resistance to ketoacidosis,Subtypes,Secondary Diabetes Pancreatic disease with resultant insulinopenia Chronic pancreatitis, pancreatectomy, CF, he
6、machromatosis Drug induced HCTZ, steroids, estrogen, psychoactive agents, catacholamines, pentamidine,Subtypes,Endocrinopathies Acromegaly, pheochromocytoma, Cushings, Conns, glucagonoma Insulin receptor abnormalities Genetic syndromes Hyperlipidemia, muscular dystrophies, Huntingtons chorea,Diagnos
7、is,Per the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 2003,Symptoms of Diabetes,Classic Polyuria, polydipsia, unexplained weight LOSS Fatigue Blurry vision Nausea, vomiting Infections,Screening for Diabetes,Every 3 years if age 45 or older (if results are normal) More
8、 frequent screening if: Pre-Diabetic Fasting plasma glucose concentration 110 mg/dL or 140/90) Dyslipidemia HDL35 mg/dL, TGL250 mg/dL,Treatment rationale,DCCTRG 39% reduction in progression of retinopathy for 0.9% reduction in HbA1c UKPDSG HbA1c of 7% associated with significant incidence of micro a
9、nd macrovascular disease,Treatment Rationale,Meticulous glucose control decreases long-term microvascular complication rates Aggressive insulin therapy in patients with a recent MI was associated with reduced mortality,Treatment of Diabetes Mellitus,Goals set by American Diabetes Association Prepran
10、dial glucose values of 80 to 120 mg/dL Bedtime glucose values of 100 to 140 mg/dL Hemoglobin A1C 7% 2 hour post-prandial glucose values 160 mg/dL,Need insulin Healthy people generally have insulin production of 24-36 units per day Type 1 DM 0.5 to 1.0 units/kg of insulin daily Varies according to di
11、et, exercise, stress Various insulin preparations with various regimens Tailor to the patient Attempt to mimic the healthy persons insulin peaks and valleys,Treatment of Type 1 Diabetes Mellitus,Rapid Acting Insulins Lispro, Aspart Short Acting Insulins Regular Intermediate Acting NPH Lente Long Act
12、ing Ultralente Glargine,Treatment of Type 1 Diabetes Mellitus,Basal/Bolus regimen,Basal/Bolus regimen Daily insulin dose consists of a basal insulin to inhibit hepatic glucose production and pre-meal insulin to cover intake mimics natural insulin production Typically this is achieved with Lantus QHS
13、 and Novolog (aspart) QAC. Patients on this regimen should either be given a Sliding scale instructing them how to cover their premeal accuchecks and how to “Carb count” OR they need a standard dose of premeal insulin which you review when you see them in clinic based on their readings. 15g carbs =
14、1 unit of insulin Requires multiple insulin injections and accuchecks, but provides greater flexibility in matching insulin to meal.,Treatment of Type 1 Diabetes Mellitus,Pancreas Transplant with or without Kidney transplant To help protect the transplanted kidney from hyperglycemia Meet certain cri
15、teria, in general, frequent, acute metabolic complications and failure with insulin therapy Survival, immunosuppression Pancreatic islet cell transplant Similar criteria Immunosuppression,Treatment of Type 2 Diabetes,Weight Loss, Diet, Exercise Decrease in body weight as little as 4-7% can help incr
16、ease insulin sensitivity United Kingdom Prospective Diabetes Study (UKPDS) 25% treated with diet and exercise alone maintain Hgb A1C 7% after 3 years and 10% after 9 years Attributed in part to progressive loss of -cell secretion of insulin Supporting evidence of dual therapy with oral agents, i.e.
17、one agent augmenting insulin secretion, another improving insulin action,Treatment of Type 2 Diabetes,Insulin Secretagogues (“Beta-beaters”) Sulfonylurea Meglitinides Biguanides decrease hepatic gluconeogenesis Metformin Thiazolidinediones insulin sensitizer The “glitizones” Alpha-glucosidase Inhibi
18、tors decreased GI absorption Acarbose,Sulfonylurea,First line after diet and exercise 20-25% primary failure rate Caution in hepatic/renal dysfunction Mechanism of action Promote increased pancreatic secretion Side effects Hypoglycemia, usually within 1st 4 months Increased in elderly, worsening ren
19、al function, irregular meal schedules Weight gain Medications Glyburide (Micronase, Diabeta) Duration of action 18-24 hours Hypoglycemia still common Glipizide (Glucotrol) Glimepiride (Amaryl) Indicated for use with insulin “safe” in renal failure,Meglitinides (rapid acting secretogogues),Theoretica
20、lly offers improved post prandial control May benefit patients with unpredictable meal schedules or large post prandial glucose levels Q meal dosing Mechanism of action Similar to sulfonylureas, quicker “on-off” action Side effects Hypoglycemia Weight gain Medications Repaglinide (Prandin) Nataglini
21、de (Starlix) Ultra short acting Most effective agent for post-prandial control Hypoglycemic contraindication with insulin,Biguanides,Weight loss due to appetite reduction Less hypoglycemia than sulfonylurea therapy Major effects: Increased hepatic insulin sensitivity Decreased gluconeogenesis and gl
22、ycogenolysis Side effects LACTIC ACIDOSIS GI intolerance Mechanism of action is unclear Medication Metformin (Glucophage) Optimal dose 2000mg/d BID dosing,Biguanides,Contraindications to metformin Serum creatinine = 1.5 mg/dL in men, = 1.4 mg/dL in women Age 75years Discontinue before any radiologic
23、 contrast studies (stop during or before) or upon hospitalization Hepatic dysfunction Dehydration Metabolic acidosis CHF requiring treatment,Thiazolidinediones (TZD),Mechanism of action Not fully understood Decrease insulin resistance, increase insulin sensitivity, probably at the peripheral skeleta
24、l muscle ? Smaller effect on liver gluconeogenesis Additive effect with metformin Favorable lipid profile effects, ? atherosclerosis Side effects Weight gain Edema caution with CHF Hypoglycemia, especially if coupled with other diabetic medication Liver dysfunction? monitor LFTs Medications Rosiglit
25、izone (Avandia) - increase HDL levels Pioglitizone (Actos) - increase HDL, decrease TG levels Contraindicated: Hepatic dysfunction Age greater than 80 Advanced CHF,Thiazolidinediones (TZD),Monotherapy or combo with metformin, sulfonylureas, and insulin Other effects: Slightly reduce BP Enhance fibri
26、nolysis Improve endothelial function,Alpha-glucosidase Inhibitors,Decreases digestion of complex carbohydrates in small bowel Slows monosaccharide absorption Effective only with diets 40% carbohydrates Lowers post-prandialpre-prandial glucose Not as efficacious as other agents (decreases A1C by 0.5%
27、 - 1%) Side effects major limitation Gas, abdominal pain, diarrhea Minimized with slow titration Medications Acarbose (Precose) Miglitol (Glyset),Oral Agent Monotherapy and Glycemic Control,Combination Oral Therapy,Lowers A1C levels by about 2% No evidence that a specific combination is any more eff
28、ective in lowering glucose levels or more effective in preventing complications than another Thus, patients with an HbA1C 9% who are receiving monotherapy are unlikely to reach a target of 7%,A 56-year-old woman who has had type 2 diabetes mellitus for 12 years is evaluated because of poorly control
29、led diabetes. She is obese (body mass index, 32 kg/m2). She takes glyburide, and over the past 6 months, her hemoglobin A1C level has increased from 6.8% to 8.5%, while measurements of her fasting plasma glucose have been greater than 200 mg/dL and postprandial measurements range from 250 to 350 mg/
30、dL. She refuses to take insulin. Which of following is the best therapy for this patient? ( A ) Discontinue glyburide and initiate metformin ( B ) Discontinue glyburide and initiate a thiazolidinedione ( C ) Continue glyburide and add metformin ( D ) Continue glyburide and repeat measurement of hemo
31、globin A1C ( E ) Continue glyburide and add acarbose,Critique (Correct Answer = C) Type 2 diabetes mellitus is a progressive disorder, and studies have documented that response to monotherapy is limited. Four options are available to obese patients who have become unresponsive to sulfonylureas: 1) a
32、dd metformin, 2) add a thiazolidinedione, 3) add an -glucosidase inhibitor, and 4) add insulin. Arguably the best treatment could be to initiate insulin at bedtime and continue the sulfonylurea. There is no consensus about which option is most effective. Adding metformin to the regimen provides an e
33、ffective agent that complements the action of sulfonylurea. Several studies document that fasting plasma glucose and hemoglobin A1C values decline with this combination of sulfonylurea and metformin in patients with body mass indexes in the range of 27 to 30 kg/m2. Maximum dosages (2000 mg) of metfo
34、rmin should be administered in divided doses. A trial of this combination for 6 to 8 weeks should determine its effectiveness. If hemoglobin A1C values do not fall to the 7.0% to 7.5% range, the patient should be encouraged to start insulin therapy. A thiazolidinedione and acarbose (an -glucosidase
35、inhibitor) are less powerful as hypoglycemic agents than sulfonylureas and metformin, and probably would be less effective in this patient than combination therapy. The patients obesity indicates that insulin resistance is a likely factor in the progressive hyperglycemia, and a thiazolidinedione war
36、rants consideration; however, if it is used, greater laboratory monitoring is required.,Oral Agent Metabolic Effects,A 52-year-old woman is found to have a fasting plasma glucose concentration of 168 mg/dL during her annual physical examination. Her lifestyle is sedentary. Obesity has been a problem
37、 since early adulthood, and her weight in recent years has ranged from 90 to 103 kg (196 to 226 lb). Her blood pressure has been elevated for the past 18 years, and while taking captopril, it is in the 160/90 to 180/100 range. The hemoglobin A1C level is 8.4%. After meeting with a dietitian and nurs
38、e educator, she starts a calorie-restricted diet and an exercise program; 6 weeks later, she weighs 91.8 kg (202 lb) and her hemoglobin A1C is 8.6%. Other laboratory tests include a total cholesterol of 238 mgldL and a fasting triglyceride level of 278 mgldL. What is the best hypoglycemic agent for
39、this patient? ( A ) Insulin ( B ) A sulfonylurea ( C ) Metformin ( D ) Acarbose ( E ) Rosiglitazone,Critique (Correct Answer = C) Persistent hyperglycemia and hypertriglyceridemia in an obese patient make metformin an ideal agent. The drug will facilitate weight loss and have beneficial effects on t
40、he hypertriglyceridemia. The United Kingdom Prospective Diabetes Study indicated that insulin and sulfonylureas equally lower plasma glucose but do not help weight loss or prevent weight gain. The thiazinolinediones as monotherapy also increase weight as well as possibly adversely affecting serum ch
41、olesterol levels. Although metformin as well as insulin and sulfonylureas reduce hyperglycemia and consequently lower the risk for the several microvascular complications, these agents do not significantly alter the risk for myocardial infarction. Insulin is most effective as the first choice in sym
42、ptomatic patients, especially those who are normal weight or only slightly overweight. In the setting of infection, a vascular accident, or other medical problem, the patient with recent-onset type 2 disease benefits from insulin as first treatment. Sulfonylureas would also probably lower plasma glu
43、cose in this patient, but weight gain or inability to lower weight are possible complications. In 10% to 15% of recently diagnosed patients, sulfonylureas are ineffective as hypoglycemic agents. The exact cause of this primary failure is unclear, although beta cells exposed to hyperglycemia for prol
44、onged periods will not respond to sulfonylureas. Acarbose is reserved for patients with type 2 diabetes mellitus in whom postprandial hyperglycemia is the major problem. In patients with elevated fasting glucose levels, acarbose will have limited effect. The thiazolidinediones effectively reduce fas
45、ting plasma glucose concentration. These agents increase serum LDL-and HDL cholesterol slightly and lower triglycerides by about 10-15%.,Which one of the following describes the effect of the thiazolidinediones? ( A ) Inducing weight loss effect ( B ) Decreasing low-density lipoprotein cholesterol (
46、 C ) Increasing production of insulin from pancreatic beta cells ( D ) Increasing glucose transporter expression,Critique (Correct Answer = D) Resistance to the action of insulin is a prime cause of the hyperglycemia in most patients with type 2 diabetes. The thiazolidinediones are a group of drugs
47、that improve sensitivity to insulin in several tissues by binding to PPAR- receptors, leading to increased expression of glucose transporters. The agent causes weight gain when used as monotherapy and in combination with insulin. Serum triglyceride values fall, whereas both LDL and HDL cholesterol v
48、alues increase; the rise in LDL cholesterol in several studies is about 10% to 15%. The currently available thiazolidinediones, rosiglitazone and proglitazone, are equally effective in lowering glucose in patients with type 2 diabetes mellitus. Hemoglobin A1C levels fall about 1.5% in studies of the
49、se agents. Several cases of severe liver toxicity have been reported after troglitazone therapy, so it was removed from the market in March of 2000. The U.S. Food and Drug Administration recommends baseline and every 2 month monitoring of liver function tests during the first year of therapy if this
50、 class of drugs is used. The incidence of elevated liver enzyme levels in patients treated with proglitazone and rosiglitazone are 0.25% and 0.2% respectively, values similar to those in patients receiving placebos.,Insulin Therapy in Type II DM,Newly diagnosed patients with DM2 have 50% of normal insulin secretion at diagnosis 25% of normal insulin secretion 6 years after diagnosis,
