Glucose Regulation

rate of action for injectable hypoglycemic drugs

-Rapid-acting - Humalog ®, Novolog ®, Apidra -Short-acting - Regular -Intermediate - NPH -Long-acting - Glargine (Lantus), Detemir (Levemir)

adipokines in developing insulin resistance in Type II DM

-Release of adipokines by adipose cells -In addition to being a store house for lipids, adipose cells secrete several substances, including proteins called adipokines. -Individuals with more adipose tissue secrete more adipokines. -Adipokines have several normal physiological functions, but when present in high quantities, they stimulate insulin resistance.

DM1 consequence on potassium uptake

-decreased potassium uptake into cells -With an insulin deficiency, potassium isn't being transported into the cell with glucose. -Increased amounts of potassium remain in the blood, potentially leading to hyperkalemia. Hyperkalemia can cause severe complications, including fatal arrhythmias.

effects of glucagon

The major effect of glucagon is to stimulate an increase in blood concentration of glucose. In response to falling serum glucose levels, glucagon has two pathways within the liver to trigger glucose release: 1. Glucagon stimulates breakdown of glycogen stored in the liver: -Acts on hepatocytes to activate enzymes that depolymerize glycogen and release glucose 2. Glucagon activates hepatic gluconeogenesis: Gluconeogenesis is the pathway by which amino acids are converted to glucose, providing a second source of glucose for the blood.

autoimmune-mediated Type 1A DM

β-cell destruction usually leading to absolute insulin deficiency Autoimmune destruction of the pancreas appears to be the primary cause of type 1A DM, when it is not secondary to other diseases. Studies show the presence of autoantibodies and cytotoxic T cells that target the beta cells, insulin, and some proteins (antigens) on the cells in the pancreatic islets.

insulin

-Insulin is the key player in control of metabolic homeostasis. -Insulin is the primary anabolic hormone responsible for limiting blood glucose and fatty acid levels. -It has a very short half life - any insulin secreted will be cleared in 15 minutes

effects of insulin on protein

-Insulin lowers amino acid levels and enhances protein synthesis -Promotes active transport of amino acids into muscles and other tissues -Decreases serum levels and provides basic materials for protein synthesis in the cells -Stimulates protein synthesis within cell, increasing protein production -Inhibits protein degradation

development of dyslipidemia in Type II DM

-Insulin resistance also affects the adipose cells. As insulin resistance develop, lipid deposition in the adipose tissue decreases and lipolysis activity increases. This lipolysis activity may not be physically obvious because most of these individuals are obese to begin with. -In most individuals, insulin resistance occurs for many years prior to the development of type 2 diabetes. This means that for many years, increasing quantities of lipids have been released into the plasma. -Upon diagnosis, most type 2 diabetics present with dyslipidemia (typically with low HDL and high triglycerides).

non-immune-mediated Type 1B DM

-Type 1B DM is less common than autoimmune. -Most of these cases occur secondary to other diseases such as chronic pancreatitis and cystic fibrosis. -Type 1B occurs mostly in people of Asian or African descent. -Affected individuals have varying degrees of insulin deficiency.

pathogenesis of Type II DM

-Type 2 diabetes results from a progressive insulin secretory defect on the background of insulin resistance -Ranges from predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance

basal/bolus insulin concept

Basal Insulin: -Suppresses glucose production so levels remain constant between meals and overnight -Meets about 50% of daily needs for insulin -May be adequate for Type 2 DM, with some endogenous insulin Bolus Insulin (Mealtime or Prandial): -Limits hyperglycemia after meals -Immediate rise and sharp peak at 1 hour -10% to 20% of total daily insulin requirement at each meal

epidemiology of diabetes mellitus

-higher risk among certain racial and ethnic groups (Asian Americans, Hispanics, non-Hispanic blacks, and American Indians) -rates increasing in young adults

insulin control of postprandial glucose level

-A large percentage of glucose absorbed from the small intestine is immediately taken up by hepatocytes. Insulin promotes the conversion of glucose to glycogen. -Main stores of glycogen are in the liver. The volume of the hepatocytes normally contains between 5% and 8% glycogen (80-100 g). -Excess glucose is used for synthesis of triglyceride

environmental causes of autoimmune-mediated Type 1A DM

-A number of environmental agents have been linked to autoimmune destruction of the pancreas. -Viral infections are an important cause of autoimmune disease. -Rubella and cytomegalovirus have both been implicated as causes of type 1A DM. -Dietary triggers include consumption of cow's milk and nitrosamines. Increased stress has been linked to the development of disease.

Glargine

-A peakless insulin with a long duration of action (nearly 24 hours) -Associated with less nocturnal hypoglycemia and lower postprandial glucose levels. -Glargine closely mimics continuous subcutaneous insulin infusion, the gold standard of basal insulin replacement -Administered once daily -In combination therapy, glargine given at bedtime; rapid- or short-acting given during the day

pre-diabetes

-A1C of 5.7%-6.4% -Fasting blood glucose of 100-125 mg/dL -OGTT 2 hour blood glucose of 140-199 mg/dL

beta cells and insulin secretion in type II DM

-Beta cell destruction and decreased insulin secretion -In later stages of the disease, many type 2 diabetics develop insulin deficiencies. -The pancreas is infiltrated by protein strands called amyloids which appear to destroy the pancreatic islets. Adipokines have also been linked to beta cell destruction. -Many type 2 diabetics eventually become type 1 diabetics who require insulin.

regulatory mechanisms of the islets

-Blood flow through the islets passes from β-cells which predominate in the center of the islet, to α- and δ-cells, which are more common at the periphery. -As a result, the first cells affected by circulating insulin released from the β-cells are the α-cells, where insulin inhibits glucagon secretion.

other oral hypoglycemics

-Chemical structures are different, but these drugs have similar effects on glucose as do biguanides and sulfonylureas. -Thiazolidinediones (-glitazone) stimulate insulin receptors on muscle, liver and fat cells -The incretin enhancers and -flozin drugs are newer classes that are reserved for use in those who have poor glucose control, since the drugs are very expensive.

glucose uptake in Type II DM

-Decreased glucose uptake into cells -Insulin resistance leads to decreased glucose uptake and hyperglycemia. -receptor down regulation -The clinical consequences of hyperglycemia in type 1 DM are the same in type 2 DM (osmotic diuresis....). (3 P's)

destruction of pancreatic beta cells

-Destruction of 80-90% of the beta cells in the pancreatic islets by autoimmune or non-immune factors leads to a clinically detectable decrease in insulin secretion. -Alpha cells are left unopposed Leads to a relative excess of glucagon. -As the proportion of insulin to glucagon in the portal vein controls hepatic glucose and fat metabolism, the abnormal levels of both contribute to hyperglycemia.

glucagon

-Glucagon is the primary "counter-regulatory" hormone that increases blood glucose through its effects on liver glucose output -Glucagon is created from the precursor preproglucagon. It circulates in an unbound form and has a short half-life (6 minutes) -Glucagon from the pancreas or the gut enters the hepatic portal vein and is carried to the liver first, so very little ever reaches systemic circulation. The liver is the primary target organ, and glucagon has very little effect on peripheral tissues.

diabetes mellitus

-Group of disorders that have glucose intolerance in common -Diabetes: term used to describe a syndrome characterized by chronic hyperglycemia and other disturbances of carb, fat, and protein metabolism

clinical manifestations for Type II DM

-Hyperglycemia -Polydipsia -Polyphagia & Weight Loss -Fatigue (Fatigue is a nonspecific, yet common, manifestation of type 2 DM. In some patients, this may be the only sign. The mechanism does not appear to have been identified.)

limitations of regular insulin

-If given immediately prior to a meal, onset of action is too slow to match the normal insulin peak and the blood glucose response to the meal is much greater than in a person without diabetes. -For best match between administration of insulin and the insulin needs that occur after eating the meal, patients are advised to administer their injection 20 to 40 minutes prior to the meal. -Inconvenient, and infrequently achieved, so poses the risk of premeal hypoglycemia if the meal is inadvertently delayed. -Duration of action of regular insulin is much longer than the normal insulin peak following meals, typically at least 6 hours and up to 12 hours when large doses are injected. -Long term high insulin levels leads to risk of hypoglycemia, which is often countered by between-meal snacks that foster weight gain in type 2 diabetes patients.

DM1 consequence on glucose uptake into cells

-If glucose cannot enter the cells, then there is a risk of cell starvation. -Amino acid uptake into cells also requires insulin. -With an insulin deficiency, the body can switch to using primarily fatty acids as a fuel source.

development of insulin resistance in type II DM

-In response to hyperinsulinemia, the target cells for insulin (i.e. almost all body cells) will down-regulate their number of insulin receptors. -Eventually the individual has so few functional receptors that the cells are unable to respond to insulin. This condition is called insulin resistance (don't have the necessary receptors). Other mechanisms associated with the development of insulin resistance include the following: -abnormalities in the membrane transport mechanisms for glucose. -post-receptor defects where the signaling pathways in insulin-dependent cells are impaired.

insulin secretion in Type II DM

-Inability to increase insulin secretion -All obese individuals have some degree of insulin resistance. -It is hypothesized that those who develop type 2 DM are unable to compensate by increasing the amount of insulin secretion by the beta cells. -This inability to compensate may be one the genetic factors associated with the development of type 2 DM.

effects of insulin on on glycogen storage in skeletal muscle

-Insulin allows skeletal muscle to import glucose for direct energy supply during activity. -Like the liver, skeletal muscle tissue also stores glycogen (~ 1% of muscle weight) because these tissues require vast quantities of glucose to make ATP for driving muscle contraction. -Relative amounts of glucose used for replenishing glycogen stores versus amount used for energy by the muscle depends on the level of physical activity during or soon after a meal.

insulin effect on catabolic processes

-Insulin is a 'building' hormone. The presence of insulin stimulates the synthesis of proteins, lipids, and carbohydrates and in turn inhibits catabolic (breakdown) processes. -Any excess nutrients not metabolized are converted to forms that can be used in other ways or stored for future use.

effects of insulin on intracellular transport of K+

-Insulin is a major regulator of potassium homeostasis and has multiple effects on sodium pump activity. -With elevated insulin secretion, sodium-potassium pumps have increased affinity for sodium and increased turnover rate. -Sustained elevations in insulin causes up-regulation of the pump. -This function of insulin is extremely important when dealing with diabetic who may not produce insulin or when administrating exogenous insulin to a diabetic. In some circumstances, injection of insulin can acutely suppress plasma potassium concentrations.

insulin effect on glucose uptake by tissues

-Insulin is required for the facilitated diffusion of glucose into many types of cells, including skeletal muscle. -The receptor for insulin is embedded in the plasma membrane, and is composed of two alpha subunits and two beta subunits. -The brain's main source of fuel is glucose. However, the CNS neurons do not require insulin for glucose uptake. So although hypoglycemia will cause CNS dysfunction and even permanent injury, low insulin levels do not. As long as there is glucose available in the plasma, the brain will be protected. -The cells of the liver also utilize a non-insulin dependent glucose transport system.

DM1 consequence on fat breakdown in adipose tissue

-Normally, insulin promotes the storage of lipid molecules in the adipose tissues. Therefore, an insulin deficiency stimulates the breakdown of fat (i.e. lipolysis) in the adipose tissue. Since glucose is unavailable in diabetics, the newly liberated fatty acids can be used as a fuel source. -The process of fat breakdown liberates a molecule called a ketone. Ketones are acidic molecules, and with rapid fat metabolism they can begin to accumulate in the blood. If the kidneys cannot excrete the ketones rapidly enough, concentrations build up causing acidosis.

hyperinsulinemia in type II DM

-Normally, insulin secretion is stimulated by the presence of elevated glucose and amino acids in the plasma. -You eat a meal with carbohydrates and/or protein, and the beta cells are stimulated to produce and secrete insulin into the blood stream. -Individuals who eat a diet high in calories, especially calories from carbohydrates and sugars, secrete large quantities of insulin. -If insulin levels are chronically high, the individual is said to have hyperinsulinemia. -When cells are exposed to high levels of a hormone, they will down regulate the number of receptors they have for this particular hormone.

DM1 consequence of osmotic diuresis

-Of the glucose that is filtered in the glomerulus, 100% is reabsorbed in the proximal convoluted tubule. That means that under normal conditions there should never be any glucose in the urine. -The amount of glucose reabsorbed is limited by the number of carrier molecules in the membrane of the PCT. -There is a level at which the carrier molecules can become saturated - that point is called the tubular maximum (Tm) or renal threshold -The Tm for glucose is 375 mg/min which corresponds to a blood glucose level of 180 mg/dL. -Individuals with diabetes who become hyperglycemic often reach the Tm for glucose reabsorption in the kidneys. -Glucose has a tendency to attract water because it has a high osmotic pressure. Any glucose remaining in the filtrate will prevent water from being reabsorbed, thus causing diuresis.

effects of insulin on cell metabolism

-Once glucose enters the cytoplasm of a cell, it can be used as a substrate for metabolism. -Insulin also plays a role in stimulating cell metabolism by increasing the activity of enzymes involved in metabolic processes. -Insulin stimulates glucose uptake and its metabolism in the cell. However, insulin is not the primary hormone of metabolism. Thyroid hormone is responsible for driving about 50% of our basal metabolic rate.

other related hormones

-Pancreatic somatostatin: produced by delta cells & essential in nutrient substrate metabolism (protein, fats, and carbs) ; may be involved in inhibiting glucagon and insulin secretion -Gastrin: poorly understood, likely controls secretion of glucagon -Ghrelin: stimulates appetite, promotes satiety and plays a role in insulin sensitivity regulation -Pancreatic polypeptide (released by F cells): released in response to hypoglycemia and protein-rich meals, promotes gastric secretion

more on basal/bolus insulin conept

-Quick-acting insulin analogues (insulin lispro and insulin aspart) have absorption profiles that more closely match normal mealtime patterns -Can be given immediately before meals, which is more convenient Quick onset of action matches normal mealtime peaks of plasma insulin better than does human regular insulin. -Clinical studies have shown that this leads to less prominent peaks of glucose after meals and less late postprandial hypoglycemia Rapid waning of the effects of mealtime lispro and aspart leads to greater dependency on adequate basal insulin levels between meals and overnight.

regular insulin

-Regular insulin is the prototype drug -Mimics endogenous insulin -Short-acting insulin -Original source of insulin was beef or pork; now all insulin is human DNA, which reduces allergies and reactions -Insulin analogs have been engineered for modified effects, such as rapid onset of action and prolonged duration

increases and decreases of insulin secretion

-Secretion increases in response to increased serum levels of glucose, amino acids, free fatty acids, and gastrointestinal hormones (gastrin, secretin, glucagon) that generally occurs after a meal, or with parasympathetic stimulation of β-cells -Decreases with low serum glucose levels, high levels of insulin or sympathetic stimulation of alpha cells

sliding scale: fast-acting insulin

-Sliding scale used to determine the dosage of insulin based on the patient's glucose reading, which should be collected just prior to a meal. -A sliding scale gives some flexibility, as the nurse can administer the dose without having to call the provider for an order. -Sliding scale insulin can also be held without an order, if appropriate -If the glucose levels get above 400, it is important to let the covering provider know, so the client can be assessed for signs of ketoacidosis.

genetic causes of autoimmune-mediated Type 1A DM

-The exact mechanisms underlying genetic susceptibility to type 1A DM are not known -18 areas of the genome have been identified as being involved -The strongest association is with HLA complex, which helps the immune systems distinguish the body's own proteins from proteins made by foreign invaders. -From a clinical perspective, it is important to note that if someone has a parent or sibling with type 1A DM, their risk of developing the disease is around 10%.

basal insulins

-The ideal basal insulin would mimic normal pancreatic basal insulin secretion, provide 24-hour effects, sustain a smooth, peakless insulin profile, and ensure reproducible, predictable effects once steady state is achieved. -Human NPH, lente, and ultralente insulin all durations of action of less than 24 hours, so they do not provide adequate basal insulin replacement for many patients. -All three, but especially NPH and lente, have pronounced peaks of action. -These limitations cause variations of glucose levels and unpredictable hypoglycemia

GLUT mechanism

-The only mechanism for cells to take up glucose is by use of glucose transporters (GLUT), the major one being GLUT4, which are activated by insulin. -When insulin concentrations are low, GLUT4 transporters are present as cytoplasmic vesicles where they are useless for glucose transport. -Binding of insulin to receptors on such cells leads to rapid fusion of the vesicle with the plasma membrane and insertion of the glucose transporters, giving the cell the ability to take up glucose.

insulin effect on synthesis of fats from fatty acids

-When the liver is saturated with glycogen, additional glucose will be used for fatty acid synthesis. -These fatty acids are exported from the liver as lipoproteins, which are reduced to free fatty acids in circulation. -Insulin facilitates entry of glucose into adipocytes, which uses it to synthesize glycerol. -Together, the glycerol and fatty acids are used by adipocytes to make triglyceride. -Insulin, then, has a fat-sparing effect. Not only does it drive the cells to preferentially oxidize carbohydrate instead of fatty acid for energy, it indirectly stimulates accumulation of fat in adipose tissue.

goal of insulin therapy

-done for all type I's and some type II's -Prevent and treat fasting and postprandial hyperglycemia -Permit appropriate utilization of glucose and other nutrients by peripheral tissues -Suppress hepatic glucose production -Mimic normal pancreatic function

risk factors for type II DM

-obesity and inactivity: truncal obesity has the highest correlation -age >40 years: incidence is rising rapidly among adolescents and young adults -ethnicity: increased incidence in Native American, Hispanic, Pacific Islander, and African Americans -family history: strong relation of genetic causes in Type II -development of insulin resistance: many complex mechanisms involved in the development of insulin resistance

Sulfonylureas

-oral hypoglycemic -First (tol-) and second (gly-) generation drugs; lower side effect profile with second generation -Stimulate release of insulin and increase sensitivity of insulin receptors on target cells. -Hypoglycemia is most common adverse effect

Biguanides

-oral hypoglycemic -Metformin is most common oral hypoglycemic agent in use -Works by decreasing hepatic glucose production and by decreasing insulin resistance. -Metformin can help the LDL/HDL ratio, which can be an added benefit for this drug. -Drug does not cause hypoglycemia, so the risk of weight gain is low, making this a very good choice for managing DMII related to obesity. -In clients who have poor renal function or those who have unstable physiologic conditions, lactic acid accumulation can occur. -This drug is often discontinued in hospitalized clients, especially when undergoing procedures

clinical manifestations: hyperglycemia

-polyuriaPolyuria Related to osmotic diuresis. Urine will also contain glucose (glycosuria). -Polydipsia: Increased serum osmolarity from hyperglycemia and dehydration from osmotic diuresis trigger thirst centers in the hypothalamus. -Polyphagia & Weight Loss: Since the cells cannot take up and metabolize glucose and amino acids, the cells starve. Individuals with undiagnosed (or untreated) type 1 DM will start to lose weight despite being hungry and eating more than normal.

oral hypoglycemics

-work to decrease insulin resistance or to stimulate the pancreas to make more insulin. -They are not helpful in type I diabetes because these individuals don't have insulin resistance, and they cannot make insulin. -Most OHAs can be hepatotoxic, although single agents at usual doses this are not a huge concern. -not effective in managing hyperglycemic emergencies, like ketoacidosis or hyperosmolar coma. -Any OHA that can cause hypoglycemia has the potential to also cause weight gain. -Most OHAs cause some GI distress, to which clients usually acclimate.

diagnostic criteria for diabetes

1. HbA1c > 6.5% 2. FPG > 126 mg/dl (7.0 mmol/L); fasting is defined as no caloric intake for at least 8 hours) OR 3. 2-hr plasma glucose > 200 mg/dl (11.1 mmol/L) during an OGTT OR 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose > 200 mg/dl (11.1 mmol/l)

effect of insulin on glucose-producing pathways

Glycogenolysis (conversion of stored glycogen back to glucose) and gluconeogenesis (process of synthesizing glucose from non-carbohydrate sources), as well as fatty acid oxidation are limited by the increased presence of insulin

secretion cells

The pancreatic Islets of Langerhans has 4 types of secretion cells that regulate carbohydrate, fat and protein metabolism: -Alpha cells: secrete glucagon -Beta cells: secrete insulin -Delta cells: secrete somatostatin -F cells: secrete pancreatic peptides Innervated by both divisions of the autonomic nervous system—parasympathetic (stimulates secretion); sympathetic (inhibits secretion)