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Advances in Diabetes Management
Leonid Poresky, M.D.
(Presented at the CAMS 2000 Semi-annual Scientific Meeting, May 21, 2000)
In the U.S., there are about 15-16 million cases of diabetes. The prevalence is about 1 in 17 individuals. Half do not know they have the disease. The majority (more than 90%) have type 2 diabetes. Diabetes is the leading cause of complications such as blindness in adults, renal failure, and non-traumatic amputations.
Etiologic classification of diabetes
mellitus
1. Type 1 diabetes: immune-mediated, characterized by insulin deficiency secondary to destruction of pancreatic islet cells.
2. Type 2 diabetes: Multifactoral etiology, ultimately involves some degree of resistance to insulin. May or may not involve absolute insulin deficiency; may or may not require treatment with insulin.
3. Other specific types of diabetes: Together, these accounts for less than 1% of diabetic patients. e.g., genetic defects of beta cell, disease of exocrine pancreas, drug or chemical-induced, infection.
4. Gestational diabetes.
Criteria for
diagnosis of type 2 diabetes:
Symptoms of diabetes (polyuria, polydipsia, unexplained weight loss) plus plasma random glucose concentration $200 mg/dl or fasting plasma glucose (FPG) $ 126 mg/dl recorded at least twice or 2-hr post-prandial glucose $200 mg/dl during an oral glucose tolerance test.
An intermediate category of diabetes, or “pre-diabetic” state, refers to patients with “impaired glucose tolerance” (2-hr post-prandial glucose on oral glucose tolerance test between 140 and 200 mg/dl, and/or “impaired fasting glucose” (between 110 and 126 mg/dl).
Pathophysiology
of type 2 diabetes
There are 3 main components
1. Peripheral insulin resistance, primarily in muscle tissue, cause unknown.
2. Impaired insulin secretion. Prolonged, compensatory hyper-secretion of insulin may lead to beta cell “burn out”.
3. Increased glucose production by liver. Higher hepatic glucose output is an import-ant but often under-appreciated mechanism of fasting hyperglycemia in diabetes.
Cellular basis of insulin action
1. Circulating insulin binds to the insulin receptor’s extracellular domain (" sub-units)
2. Binding of insulin shifts the receptor conformation.
3. Intracellular (beta) subunits are phosphorylated, activating a phosphorylation cascade inside the cell.
4. The signaling cascade ultimately leads to the translocation of glucose transporters from the cell interior to the plasma membrane.
5. Glucose transporters permit the entry of glucose into the cell.
6. There are many potential sites in this pathway (or other pathways) for errors that may give rise to type 2 diabetes. We still do not know where the “primary” error is, if there is one.
Mechanism of the pathogenesis of type 2 diabetes
1. Insulin resistance is probably the initiating event, with multifactorial causes: Genetic, environmental/ behavioral (obesity, aging, sedentary lifestyle).
2. Hyperinsulinemia develops, mainly a compensatory response by the pancreas to insulin resistance. Initially, glucose tolerance remains normal because of high insulin production.
3. Progression to impaired glucose tolerance when insulin secretion falls.
4. Beta cell failure, or frank type 2 diabetes, characterized by increased insulin resistance, increased hepatic glucose output, and decreased insulin secretion.
Summary:
(a) Peripheral insulin resistance is probably the primary derangement in type II diabetes. Hyperinsulinemia and increased hepatic glucose output are compensatory events.
(b) Hyperglycemia is the clinical derangement leading to diabetic complications. Microvascular complications (retinopathy, nephropathy, neuropathy) begin to appear, on average, by 7 to 10 years.
Treatment
rationale
Tight glucose control in type 2 diabetes is supported by compelling new data. The ADA targets for metabolic control of diabetes are:
1. Achieve a fasting blood glucose of 80-120 mg/dl, or a post-prandial glucose of <160 mg/dl.
2. Achieve and maintain HbA1c of 7% or less.
3. Total cholesterol should be <200 mg/dl.
4. Triglyceride should be <200 mg.dl.
5. Achieve a body mass index of <25 kg/m2
Glucose monitoring is essential Every diabetic patient should do it. Number of tests and time of measurement may vary. As internists treat the majority of diabetic patients (endocrinologists treat only about 5%), internist must therefore aggressively promote tight glucose control.
Approach
to therapy
A stepwise approach is most effective.
1. Nutrition and diet.
2. Add oral anti-hyperglycemic agents., monotherapy or combined therapy.
3. Change to insulin.
4. Intensify insulin therapy.
Diet: The ADA has eliminated targets for daily carbohydrate intake, and has developed new recommendations for diabetic diets:
Saturated fat should be <10% of calories.
1. An additional 10% of calories may come from polyunsaturated fat.
2. Cholesterol must be < 300 mg per day.
3. Daily recommended fiber intake is 30 g.
4. Protein and carbohydrates may be added in any combination, guidelines should be individualized base on the patient’s blood sugar, lipid profile, food preference, presence or absence of renal failure etc.
Exercise: Exercise is important. If a patient would exercise aerobically 40 min per day, 5 days a week, medication may not be necessary for a large number of them. Potential benefits of exercise are:
1. Improves cardiovascular risk factor.
2. Augments weigh reduction efforts.
3. Improves glucose control by increasing insulin sensitivity.
4. Reduces dosage or need for insulin or hypoglycemic agents.
Oral antihyperglycemics: Several classes, each with a different mechanism of action(see below). Combinations are usually more effective than monotherapy.
When oral agents alone fail, add insulin at bedtime to suppress nocturnal hepatic glucose output; or, switch to insulin alone.
Intensification of insulin therapy can be done with insulin pumps.
Sulfonylureas- stimulate insulin secretion from islet cells, effective and widely used
1.
First generation (seldomly used now): chlopropamide (Diabinese), tolbuta-mide (Orinase),
tolazamide (Tolinase).
2. Second generation, more potent. Glyburide (Micronase or Diabeta), glipizide (Glu cotrol, Glucotrol-XL).
3. New: Glimepiride (Amaryl), a second generation sulfonylurea, longer acting (once a day dosing) , can be combined with insulin, reducing the amount of insulin used.
4. 70% of patients are indefinitely controlled on sulfonylureas; 30% of patients fail, due to beta cell exhaustion.
1. Mechanism of action: Inhibit hepatic glucose output (major effect) and reduce peripheral insulin resistance in muscle (minor effect).
2. Secondary rate of failure is about the same as sulfonylureas alone.
3. Combined use with diet or a sulfonylurea can be very effective. In a patient failing sulfonylureas the first step is to add metformin. Caution: the combination may cause hypoglycemia.
4. Dosing: 500 and 850 mg bid or t.i.d. up to 2500 mg/day.
5. Problems: Lactic acidosis, especially in patients with liver or kidney dysfunction. Contraindicated in patients with alcohol abuse, with anticipated surgery or the use of radiologic contrast agents that may interfere with renal function. G.I. side effects: generally mild and self-limiting.
Sulfonylurea
Dosing interval starting max dose dose Glipizide- GIPS qd 5 mg 20 mg Glimepiride qd 1.2 mg 8 mg Glyburide qd-bid 2.5 mg 20 mg Glynase qd-bid 3 mg 12 mg |
Alpha-Glucosidase
inhibitors: Acarbose (Precose)
1. Acts in the GI tract as a competitive inhibitor of brush-border enzymes ("-glucosidases), thus slowing polysaccharides absorption. Polysaccharides digestion is redistributed from proximal to distal GI tract.
2. Attenuates post-prandial hyperglycemia.
3. Can be added to diet, sulfonylureas, or metformin.
4. Problems: Poorly tolerated, flatulence may be severe. Titrate the dose.
Thiazolidinediones: Rosiglitazone (Anandia), Pioglitazone (Actos) Troglitazone (Rezulin) is off the market.
1. Mechanism of action: act at a novel nuclear receptor called PPAR-gamma. Reduces insulin resistance in the muscle, thereby increasing glucose uptake (major effect), and reduce hepatic glucose output (minor effect).
2. Clinical data: glucose reduction at lower insulin levels, i.e., enhanced insulin sensitivity, in both diabetic and non-diabetic patients.
3. Can be used alone or in combination with sulfonylureas or with insulin.
4. Long time to onset, 2-3 weeks.
5. Side effects: Possibly improve fertility, reduction in effectiveness of some oral contraceptives. Use with caution in patients with congestive heart failure and hepatic dysfunction.
Benzoic Acid Analogs: Repaglinide (Prandin)
1. A sulfonylurea type agent that increases insulin secretion.
2. Rapid onset (0.7 hr to peak) and short half-life (1 hr); should be taken immediately before meals.
3. Excreted by bile, can be used safely in patients with renal insufficiency.
4. Disadvantages: risk of hypoglycemia, weight gain.
Insulin
1. 30% of type 2 diabetics become insulin deficient and require exogenous insulin. Insulin resistance is the early initiating event in the development of type 2 diabetes. In response to insulin resistance and decreased cellular glucose uptake, hepatic glucose output rises, resulting in impaired glucose tolerance. Patient must then produce more insulin to maintain normal plasma glucose levels. They have a higher insulin response than normals. As diabetes progresses, beta-cell function diminishes, insulin secretion falls off, and the patient requires exogenous insulin.
2. Insulin Lispro (Humalog) - an insulin analog. It is designed to attenuate post-prandial hyperglycemic peaks. In Lispro, two amino acids, lysine and proline, at positions 28 and 29, are switched. The switch changes insulin polymerization. In order to work, insulin must be monomeric. Regular insulin, polymeric in solution, must achieve extremely low concentrations in the subcutaneous tissue (10-8 M) to depolymerize which takes time. Lispro rapidly achieves a monomeric state (depolymerization occurs at 10-3 M), thus a shorter time to onset.
Human
Insulin Action (hrs) Onset Peak Duration Regular 0.5 2 6* NPH 2 6 14* Lente 2 7 14* Ultralente 3 8 18* 70/30 0.5 4 12* 50/50 0.5 3 12* Lispro 0.1 1 # *dose dependent |
1.
Risk factors for diabetes: Obesity: $120% of ideal by wt. Family history
(first degree relatives), Ethnic minority groups, History of gestational
diabetes or delivery of a baby > 9lbs, BP >140/90 mm Hg, HDL #35 mg/dl and or TG $ 200 mg/dl.
2. Current recommendations -
Screening: all patients over 45 should have FPG, if normal (<110 mg/dl), repeat in 3 yrs. Patient with risk factor(s) should be screened yearly.
Tests: FPG is sufficient.
(Dr. Leonid Poresky is Director of
Diabetes Center and Professor of Medicine at the Weill Medical College of Cornell
University)
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