Diabetes and Drugs 2024 PDF

DIABETES AND DRUGS 40-1 the Pancreas Pancreas is both an endocrine and exocrine gland – Secretes several enzymes into the duodenum for digestion of nutrients (exocrine) – Secretes insulin when blood glucose increases and glucagon when blood glucose decreases (endocrine) 40-3 40-4 Glucose homeostasis...

DIABETES AND DRUGS 40-1 the Pancreas Pancreas is both an endocrine and exocrine gland – Secretes several enzymes into the duodenum for digestion of nutrients (exocrine) – Secretes insulin when blood glucose increases and glucagon when blood glucose decreases (endocrine) 40-3 40-4 Glucose homeostasis Insulin Beta cells of pancreas stimulated to release insulin into the blood High blood glucose level STIMULUS: Rising blood glucose level (e.g., after eating a carbohydrate-rich meal) Body cells take up more glucose Liver takes up glucose and stores it as glycogen Homeostasis: Normal blood glucose level (about 90 mg/100 mL) Blood glucose level rises to set point; stimulus for glucagon release diminishes Figure 26.8 Blood glucose level declines to a set point; stimulus for insulin release diminishes Liver breaks down glycogen and releases glucose to the blood STIMULUS: Declining blood glucose level (e.g., after skipping a meal) Alpha cells of pancreas stimulated to release glucagon into the blood Glucagon Normal Glucose Control In the post-absorptive period of a normal individual, low basal levels of circulating insulin are maintained through constant β cell secretion. This suppresses lipolysis, proteolysis and glycogenolysis. After ingesting a meal a burst of insulin secretion occurs in response to elevated glucose and amino acid levels. When glucose levels return to basal levels, insulin secretion returns to its basal level. Type I DM: Lack of functional β-cells prevents mitigation of elevated glucose levels and associated insulin responses. The onset and progression of neuropathy, nephropathy and retinopathy are directly related to episodic hyperglycemia. Type II DM: The pancreas retains some β-cell function but effective insulin response is inadequate for the glucose level. Actual insulin levels may be normal or supra-normal but it is ineffective (insulin resistance). Diabetes Mellitus Group of metabolic diseases Is a deficiency in insulin secretion or decreased sensitivity of insulin receptors Results in hyperglycemia Includes Type 1 and Type 2 Diabetes Mellitus This is a disease caused by elevated glucose levels 2 Types of diabetes: Type I diabetes (10% of cases) – Develops suddenly, usually before age 15. – Caused by inadequate production of insulin because T cell-mediated autoimmune response destroys beta cells. – Controlled by insulin injections. Type II diabetes (90% of cases) – Usually occurs after age 40 and in obese individuals, but genetics, aging, and peripheral insulin resistance also. – Insulin levels are normal or elevated but there is either a decrease in number of insulin receptors or the cells cannot take it up. – Controlled by dietary changes and regular exercise. Table 24-8. Type 1 Versus Type 2 Diabetes Mellitus (DM) Clinical Type 1 DM Onset: 30 years Obese Increased blood insulin (early);normal to moderate decreased insulin (late) No anti-islet cell antibodies Ketoacidosis rare; nonketotic hyperosmolar coma 50-90% concordance in twins No HLA linkage Linkage to candidate diabetogenic genes (PPARγ, calpain 10) Insulin resistance in skeletal muscle, adipose tissue and liver β-cell dysfunction and relative insulin deficiency No insulitis Focal atrophy and amyloid deposition Mild β-cell depletion Type II Diabetes Mellitus Causes – Lack of sensitivity of insulin receptors at target cells (insulin resistance) – Deficiency in insulin secretion If untreated, results in same chronic conditions as type 1 DM 40-11 Type 2 Diabetes:Pathophysiology Exxagerated lipolysis I I βCell Dysfunction Insulin Pancreas I Increased hepatic glucose output Decreased Glucose Uptake Insulin Resistance Progression to type 2 diabetes Normal IGT* Type 2 diabetes Insulin resistance Increased insulin resistance Insulin secretion Hyperinsulinemia, then -cell failure Postprandial glucose Abnormal glucose tolerance Fasting glucose Hyperglycemia *IGT = impaired glucose tolerance Adapted from Type 2 Diabetes BASICS. International Diabetes Center (IDC), Minneapolis, 2000. Duration of Diabetes Signs and Symptoms of Hyperglycemia Hyperglycemia can result from underdose of insulin or oral hypoglycemic Fasting blood glucose greater than 7.0 mmol/L Polyuria, polydipsia, polyphagia Glucosuria, weight loss/gain, fatigue 40-15 Long term complications The long term complications of diabetes may be divided into two large groups: 1. Macrovascular: These complications are associated with pathology of the large and medium-sized vessels; this includes CHD, stroke, Peripheral vascular disease (PVD). 2. Microvascular: These complications are due to vascular pathology of the small vessels and include neuropathy, nephropathy, retinopathy Treatment: Type I: Type 1s depend on exogenous insulin to prevent hyperglycemia and avoid ketoacidosis. The goal of type 1 therapy is to mimic both the basal and reactive secretion of insulin in response to glucose levels avoiding both hyper- and hypo-glycemic episodes. Type II: The goal of treatment is to maintain glucose concentrations within normal limits to prevent long term complications. Weight reduction, exercise (independent of weight reduction) and dietary modification decrease insulin resistance and are essential steps in a treatment regimen. For many this is inadequate to normalize glucose levels, the addition of hypoglycemic agents is often required, often insulin therapy is required. INSULIN THERAPY INSULIN Insulin is a peptide hormone synthesized as a precursor (pro-insulin) which undergoes proteolytic cleavage to form a dipeptide; the cleaved polypeptide remnant is termed protein C. Both are secreted from the β-cell, normal individuals secrete both insulin and (but much less) pro-insulin. Type 2s are found to secrete high levels of pro-insulin (pro-insulin is inactive) measuring the level of Cprotein is a more accurate estimation of normal insulin secretion in type 2s. INSULIN RELEASE The synthesis and release of insulin is modulated by: 1. Glucose (most important), AAs, FAs and ketone bodies stimulate release. 2. Glucagon and somatostation inhibit relases 3. α-Adrenergic stimulation inhibits release (most important). 4. β-Adrenergic stimulation promotes release. 5. Elevated intracellular Ca2+promotes release. Insulin secretion - Insulin secretion in beta cells is triggered by rising blood glucose levels. Starting with the uptake of glucose by the GLUT2 transporter, the glycolytic phosphorylation of glucose causes a rise in the ATP:ADP ratio. This rise inactivates the potassium channel that depolarizes the membrane, causing the calcium channel to open up allowing calcium ions to flow inward. The ensuing rise in levels of calcium leads to the exocytotic release of insulin from their storage granule. Insulin secretion: Insulin secretion is regulated by glucose levels, certain amino acids, hormones and autonomic mediators. Secretion is most commonly elicited by elevated glucose levels; increased glucose levels in β-cells results in increased ATP levels, this results in a block of K+channels causing membrane depolarization which opens Ca2+channels. The influx of Ca2+results in a pulsatile secretion of insulin; continued Ca2+influx results in activation of transcription factors for insulin. Oral glucose elicits more insulin secretion than IV glucose; oral administration elicits gut hormones which augment the insulin response. Insulin is normally catabolized by insulinase produced by the kidney. Types of Insulin Insulin was discovered in 1921 by Canadians Banting and Best Until the 1980s insulin came from beef or pork Today, most is human insulin, obtained through DNA technology – More effective, fewer allergies, less resistance – Modified to be more rapid (Humalog) or have prolonged action (Lantus) 40-24 Types of Insulin Doses and routes are highly individualized for each client Insulin preparations vary by: – Onset of action – Time to peak effect – Duration – Routes of administration Subcutaneous , Insulin pump, Dry powder inhaler, Intravenous (Only regular insulin can be given intravenously) 40-25 Insulin Preparations 40-26 Insulin Human insulin consists of 51aain two chains connected by 2 disulfide bridges (a single gene product cleaved into 2 chains during post-translational modification). T1/2~5-10 minutes, degraded by glutathione-insulin transhydrogenase (insulinase) which cleaves the disulfide links. Bovine insulin differs by 3aas, pork insulin differs by 1aa. Insulin is stored in a complex with Zn2+ions. Effects of insulin Rapid (seconds): Increased transport of glucose, amino acids, and K+ into insulin sensitive cells. Intermediate (minutes): Stimulation of protein synthesis Inhibition of protein degradation Activation of glycogen synthase and increased glycogenesis Inhibition of phosphorylase and gluconeogenic enzymes (decreased gluconeogenesis) Delayed actions (hours): Increase in mRNAs for lipogenic and other enzymes (increased lipogenesis) On carbohydrate metabolism.. Reduces rate of release of glucose from the liver by inhibiting glycogenolysis stimulating glycogen synthesis stimulating glucose uptake stimulating glycolysis inhibiting gluconeogenesis Increases rate of uptake of glucose into all insulin sensitive tissues, notably muscle and adipose tissue. On lipid metabolism… Reduces rate of release of free fatty acids from adipose tissue. Stimulates de novo synthesis of fatty acids and also conversion of fatty acids to triglycerides in liver. On protein metabolism… Stimulates transport of free amino acids across the plasma membrane in liver and muscle. Stimulates protein synthesis and reduces release of amino acids from muscle. Actions…… Insulin favors movement of potassium into cells. Vigorous treatment with insulin (as in DKA) will cause potassium to move into cells causing hypokalemia. Promotes general growth and development. Insulin Na+ Sodium Potassium ATPase K+ CELL IGF Substances with insulinlike activity include IGF I and IGF II (insulin like growth factors) also called somatomedins. They are secreted by liver, cartilage and other tissues in response to growth hormone. The IGF receptor is very similar to insulin receptor. Glucose transporters Glucose enters cells by facilitated diffusion with the help of glucose transporters, GLUT 1 to GLUT 7 GLUT 4 is the glucose transporter in muscle and adipose tissue which is stimulated by insulin Transport of glucose into the intestine and kidneys is by secondary active transport with sodium i.e. via sodium dependent glucose transporters Major factors regulating insulin secretion Direct feedback effect of plasma glucose on β cells of pancreas http://biomed.brown.edu/Courses/BI108/BI108_2002 _Groups/pancstems/stemcell/pancreas.gif Major factors regulating insulin secretion…. Drugs Tolbutamide and other sulfonylurea derivatives. Biguanides (Metformin or Glyciphage) decrease hepatic gluconeogenesis Thiazolidinediones (Rosiglitazone etc) increase insulin sensitivity by activating Peroxisome Proliferator-Activated Receptor (PPARγ) receptors in the cell nucleus Sympathetic nerve stimulation to pancreas → inhibition of insulin secretion Parasympathetic stimulation to pancreas → increase in insulin secretion Major factors regulating insulin secretion….. Orally administered glucose has a greater insulin stimulating effect than intravenously administered glucose This led to the possibility that certain substances secreted by the gastrointestinal mucosa stimulated insulin secretion. Glucagon, glucagon derivatives, secretin, cholecystokinin and gastric inhibitory peptide, all have such an action. INCRETIN Effect = The increase of insulin secretion after oral as opposed to intravenous administration of glucose. The two most important Incretin hormones: Glucose-dependent insulino-tropic polypeptide (GIP), formerly known as gastric inhibitory polypeptide Glucagon-like peptide (GLP-1), an additional gut factor that stimulates insulin secretion. Glucagon-like polypeptide 1 (GLP-1) GLP-1 is synthesized within L cells located predominantly in the ileum and colon, and a lesser number in the duodenum and jejunum. GLP-1 stimulates insulin secretion, suppresses glucagon secretion, slows gastric emptying, reduces food intake, increases β cell mass, maintains β cell function, improves insulin sensitivity and enhances glucose disposal. The glucose lowering effects of GLP-1 are preserved in type 2 diabetics. However, native GLP-1 is rapidly degraded by dipeptidyl peptidase- IV(DPP-IV) after parenteral administration. GLP-1 receptor (GLP-1R) agonists and DPP-IV inhibitors have shown promising results in clinical trials for the treatment of type 2 diabetes. Mechanism of Insulin Action Insulin binds to specific high affinity membrane receptors with tyrosine kinase activity Phosphorylation cascade results in translocation of Glut-4 (and some Glut-1) transport proteins into the plasma membrane. It induces the transcription of several genes resulting in increased glucose catabolism and inhibits the transcription of genes involved in gluconeogenesis. Insulin promotes the uptake of K+into cells. Action of Insulin on Various Tissues Liver Muscle Adipose ↓ glucose production ↑ Glucose transport ↑ glucose transport ↑ glycolysis ↑ glycolysis ↑ lipogenesis& lipoprotein lipase activity ↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis ↑ Protein synthesis ↑ protein synthesis The Goal of Insulin Therapy Administration of insulins are arranged to mimic the normal basal, prandial and post-prandial secretion of insulin. Short acting forms are usually combined with longer acting preparations to achieve this effect. Rapid Onset and Ultrashort-acting Preparations 1. Regular insulin: short acting, soluble, crystalline zinc insulin is usually given subcutaneously; it rapidly lowers glucose levels. All regular insulin is now made using genetically engineered bacteria; cow and pig no longer used. 2. Lispro, Aspart&Glulisine preparations are classified as ultrashort acting forms with onset more rapid than regular insulin and a shorter duration. These are less often associated with hypoglycemia. Lispro insulin is given 15 minutes prior to a meal and has its peak effect 30-90 minutes after injection (vs. 50-120 minutes for regular insulin). 3. Glulisine can be given anywhere from 15 minutes prior to 20 minutes after beginning a meal. Intermediate –acting Insulin Preparations 1. Lente insulin: This is a amorphous precipitate of insulin with zinc ion combined with 70% ultralente insulin. Onset is slower but more sustained than regular insulin. It cannot be given IV ( this has not been produced since 2005). 2. Isophane NPH insulin: Neutral protamine Hagedorn insulin is a suspension of crystalline zinc insulin combined with protamine (a polypeptide). The conjugation with protamine delays its onset of action and prolongs it effectiveness. It is usually given in combination with regular insulin. Prolonged-acting insulin preparations 1.Ultralente: a suspension of zinc insulin forming large particles which dissolve slowly, delaying onset and prolonging duration of action. 2.Insulin glargine: Precipitation at the injection site extends the duration of action of this preparation. 3. Detemir insulin: has a FA complexed with insulin resulting in slow dissolution. Pump vs. Standard Insulin Therapy Insulin Preparations and Treatment Various types of insulin are characterized by their onset and duration of action Insulin Combinations Various premixed combinations of various preparations of insulin are available to ease administration. Standard combination use should follow establishment of an acceptable regime of individual preparations. Adverse Effects of Insulin 1. Hypoglycemia may occur due to insulin overdose, insufficient caloric intake (missed meal, improper meal content, delayed meal, etc.). Ethanol consumption promotes hypoglycemic response. Symptoms: ↑ HR, diaphoresis. 1. Hypokalemia: insulin draws K+into the cell with glucose (hyperglycemia with normal K+). 2. Anaphylaxis: when sensitized to non-human insulin gets nonhuman insulin (now rare). 3. Lipodystrophy at injection site 4. Weight gain 5. Injection complications Signs and Symptoms of Hypoglycemia Hypoglycemia can result from – Insulin overdose – Improper timing of insulin dose – Skipping a meal Signs and Symptoms – Tachycardia, confusion – Sweating, drowsiness – Convulsions, coma, death 40-52 Treatment of Type 2 Diabetes Mellitus Type 2 Diabetes Mellitus is controlled through: – lifestyle changes – oral hypoglycemic drugs lower blood-glucose levels have potential to cause hypoglycemia are not effective for type 1 DM 40-53 Oral Hypoglycemics These agents are useful in the treatment of type 2s who do not respond adequately to non-medical interventions (diet, exercise and weight loss). Newly diagnosed Type 2s (less than 5 years) often respond well to oral agents, patients with long standing disease (often diagnosed late) often require a combination of agents with or without insulin. The progressive decline in β-cell function often necessitates the addition of insulin at some time in Type II diabetes. Oral agents are never indicated for Type Is. Drug Classes to Treat Type 2 Diabetes Classes of Oral Hypoglycemic Drugs – Sulfonylureas – Biguanides – Thiazolidinediones – Alpha-glucosidase inhibitors – Meglitinides 40-55 SUPHONYLUREAS Sulfonylureas Stimulate release of insulin from pancreatic islet cells Increase sensitivity of insulin receptors on target cells Most common adverse effect is hypoglycemia – Usually caused by taking too much medication or not eating enough food 40-57 Sulfonylureas These agents promote the release of insulin from β-cells (secretogogues); tolbutamide, glyburide, glipizide and glimepiride. Mechanism: – Bind to the SUR1 subunit and block the ATP-sensitive K+ channel in the beta-cell membrane – These agents require functioning β-cells, they stimulate release by blocking ATPsensitive K+channels resulting in depolarization with Ca2+influx which promotes insulin secretion. – They also reduce glucagon secretion and increase the binding of insulin to target tissues. – They may also increase the number of insulin receptors Pharmacokinetics: These agents bind to plasma proteins, are metabolized in the liver and excreted by the liver or kidney. Tolbutamide has the shortest duration of action (6-12 hrs) the other agents are effective for ~24 hrs. Sulfonylureas Adverse Effects: These agents tend to cause weight gain, hyperinsulinemia and hypopglycemia. Hepatic or renal insufficiency causes accumulation of these agents promoting the risk of hypoglycemia. There are a number of drug-drug interactions. Elderly patients appear particularly susceptible to the toxicities of these agents. Tolbutamide is asociated with a 2.5X ↑ in cardiovascular mortality (banned in Canada). Onset and Duration Short acting: Tolbutamide (Orinase) Intermediate acting: Tolazamide (Tolinase), Glipizide (Glucotrol), Glyburide (Diabeta) Long acting: Chloropropamide, Glimerpiride DRUG INTERACTIONS Biguanides Metformin is classified as an insulin sensitizer, it increases glucose uptake and utilization by target tissues. It requires the presence of insulin to be effective but does not promote insulin secretion. The risk of hypoglycemia is greatly reduced. Mechanism: Metformin reduces plasma glucose levels by inhibiting hepatic gluconeogenesis. It also slows the intestinal absorption of sugars. It also reduces hyperlipidemia (↓LDL and VLDL cholesterol and ↑ HDL). Lipid lower requires 4-6 weeks of treatment. Metformin also decreases appetite. It is the only oral hypoglycemic shown to reduce cardiovascular mortality. It can be used in combination with other oral agents and insulin. Adverse effects: Hypoglycemia occurs only when combined with other agents. Rarely severe lactic acidosis is associated with metformin use particularly in diabetics with CHF. Drug interactions with cimetidine, furosemide, nifedipine and others have been identified. AMP Kinase: Metabolic roles Role of metformin in hepatocyte Metformin enters the cell through transporters such as SLC22A1 and inhibits mitochondrial complex I. Complex I inhibition results in reduced ATP levels and an accumulation of AMP. As a result, Gluconeogenesis is suppressed as a result of reduced activity of enzymes involved in the gluconeogenic flux and reduced gene expression Metformininduced change in energy charge also activates AMPK, which suppresses fat metabolism and possibly also contributes to the reduced gluconeogenic gene expression. SLC22A1, solute carrier family 22 member 1. α-Glucosidase Inhibitors Acarbose and miglitol are two agents of this class used for type 2 diabetes. Mechanism of action: These agents are oligosaccharide derivatives taken at the beginning of a meal delay carbohydrate digestion by competitively inhibiting αglucosidase, a membrane bound enzyme of the intestinal brush border. Pharmacokinetics: Acarbose is poorly absorbed remaining in the intestinal lumen. Migitol is absorbed and excreted by the kidney. Both agents exert their effect in the intestinal lumen. Adverse Effects: GUESS (flatulence, diarrhea, cramping). Metformin bioavailability is severely decreased when used concomitantly. These agents should not be used in diabetics with intestinal pathology. Alpha-glucosidase hydrolyses oligosaccharides to monosaccharides which are then absorbed. Acarbose also inhibits pancreatic amylase. The normal post-prandial glucose rise is blunted, glucose levels rise modestly and remain slightly elevated for a prolonged period, less of an insulin response is required and hypoglycemia is avoided; use with other agents may result in hypoglycemia.. Insulin Sensitizers Thiazolidinediones (Glitazones) These agents are insulin sensitizers, they do not promote insulin secretion from β-cells but insulin is necessary for them to be effective. Pioglitazone and rosiglitazone are the two agents of this group. Thiazolidinediones Reduce blood glucose by decreasing insulin resistance and inhibiting hepatic gluconeogenesis Optimal lowering of blood glucose may take 3 to 4 months of therapy Most common adverse effects: fluid retention, headache, weight gain Hypoglycemia does not occur with drugs in this class Mechanism of Action: These agents act through the activation of peroxisome proliferator-activated receptor-γ (PPAR-γ). Ligands for PPAR-γ regulate adipocyte production, secretion of fatty acids and glucose metabolism. Agents binding to PPAR-γ result in increased insulin sensitivity is adipocytes, hepatocytes and skeletal muscle. Hyperglycemia, hypertriglyceridemia and elevated HbA1c are all improved. HDL levels are also elevated. Accumulation of subcutaneous fat occurs with these agents. In the liver: ↓glucose output In muscle: ↑glucose uptake In adipose: ↑glucose uptake , ↓FA release Only pioglitazone may be used in combination with insulin; the insulin dose must be modified. Rosiglitazone may be used with other hypoglycemic but severe edema occurs when combined with insulin. Pharmacokinetics: Both are extensively bound to albumin. Both undergo extensive P450 metabolism; metabolites are excreted in the urine the primary compound is excrete unchanged in the bile. Adverse Effects: Fatal hepatotoxicity has occurred with these agents; hepatic function must be monitored. Oral contraceptives levels are decreased with concomitant administration, this has resulted in some pregnancies. MEGLITINIDES Newer class of oral hypoglycemics Act by stimulating release of insulin from pancreatic islet cells Both agents in this class have short durations of action of 2–4 hours Efficacy equal to that of sulfonylureas Well tolerated Hypoglycemia most common adverse effect 40-69 Meglitinide analogs These agents [repaglinide (Prandin) and nateglinide (Starlix)] act as secretogogues. Mechanism: These agents bind to ATP sensitive K+channels like sulfonylureas acting in a similar fashion to promote insulin secretion however their onset and duration of action are much shorter. They are particularly effective at mimicking the prandial and post-prandial release of insulin. When used in combination with other oral agents they produce better control than any monotherapy. Pharmacokinetics: These agents reach effective plasma levels when taken 10-30 minutes before meals. These agents are metabolized to inactive products by CYP3A4 and excreted in bile. Adverse Effects: Less hypoglycemia than sulfonylureas; drugs that inhibit CYP3A4 (ketoconozole, fluconazole, erythromycin, etc.) prolong their duration of effect. Drugs that promote CYP3A4 (barbiturates, carbamazepine and rifampin) decrease their effectiveness. The combination of gemfibrozil and repaglinide has been reported to cause severe hypoglycemia. Incretin Therapy Incretins are naturally occurring hormones that the gut releases throughout the day; the level of active incretins increases significantly when food is ingested. Endogenous incretins GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide) facilitate the response of the pancreas and liver to glucose fluctuations through their action on pancreaticβcells andαcells. GIP and GLP-1 are the 2 major incretin hormones in humans: 1 – GIP is a 42-aa peptide derived from a larger protein (ProGIP) and is secreted by endocrine K cells mainly present in the proximal gastrointestinal (GI) tract (duodenum and proximal jejunum). – GLP-1 is a 30- or 31-aa peptide derived from a larger protein (proglucagon) and is secreted by L cells located predominantly in the distal GI tract (ileum and colon). This protein was first isolated from salivary gland venom of the Gila monster (investigating how these lizards are able to tolerate long periods between meals). Incretin Therapy Januvia (sitagliptin) These incretins are released from the gut in response to ingestion of food and collectively contribute to glucose control by: Stimulating glucose-dependent insulin release from pancreatic beta cells (GLP-1 and GIP): Decreasing glucagon production from pancreatic alpha cells (GLP-1) when glucose levels are elevated. The combination of increased insulin production and decreased glucagon secretion reduces hepatic glucose production when plasma glucose is elevated. The physiologic activity of incretins is limited by the enzyme dipeptidyl peptidase-4 (DPP-4), which rapidly degrades active incretins after their release. The Incretin Effect Is Diminished in Type 2 Diabetes Levels of GLP-1 are decreased. The insulinotropic response to GIP is diminished but not absent. Defective GLP-1 release and diminished response to GIP may be important factors in glycemicdysregulation in type 2 diabetes. SIDE EFFECTS Standardvs. Intensive Treatment Type Normal Standard Intensive Glucose Goal 110mg/dl 225-275 mg/dl 150 mg/dl HbA1c Goal 6% 8-9% 7% Treatments -----------Insulin BID 3 or more BG Monitoring -------------2-3 per day 4-6 per day The trade off between standard and intensive therapy is more frequent hypoglycemic events (hypoglycemic events, seizures and coma) for a marked delay in the onset of diabetic complications both microvascular and macrovascular. HbA1c = Hemoglobin A1c is a useful measure of glucose control over the prior 3-6 months, hyperglycemic episodes result in the nonspecific glycosylation of various proteins.