Glucose regulation

Destruction of pancreatic beta cells in type 1

-destruction of 80-90% of beta cells in 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 proportion of insulin to glucagon in portal vein controls hepatic glucose and fat metabolism, the abnormal levels of both contribute to hyperglycemia

clinical consequences of type 2: decreased glucose uptake into cells

-insulin resistance leads to decreased glucose uptake and hyperglycemia -osmotic diuresis, same as in type 1

clinical consequences of type 2: Beta cell destruction and decreased insulin secretion

in later stages of disease, many type 2 diabetics develop insulin deficiencies -pancreas is infiltrated by protein strands called amyloids, destroy pancreatic islets. Adipokines also linked to beta cell destruction -

intermediate acting insulin

onset: 1-2 hours peak: 4-12 hours duration: 18-24 hour ex: NPH (Humalin-N)

Rapid acting insulin

onset: 15' peak: 30-60 minutes, up to 3 hours duration: 3-4 hours ex: Lispor (Novolog), Aspart (Humalog)

short acting insulin

onset: 30-60' peak:2-3 hours duration: 5-7 hours ex: Regular (Humalin-N)

Sustained

onset: 60', gradual peak: none duration: 24 hours ex: Glargine (lantus), Detemir (Levimir)

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

Other hypoglycemic drugs

-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.

Pancreatic cells

-Islets of Langerhans have 4 types of secretion cells that regulate carbohydrate, fat and protein metabolism 1. Alpha cells: secrete glucagon 2. beta cells: secrete insulin 3. Delta cells: secrete somatostatin 4. F cells: secrete pancreatic peptides -innervated by both parasympathetic (stimulates secretion, AND sympathetic (inhibits secretion)

patho of type 2: inability to increase insulin secretion

-all obese individuals have some degree of insulin resistance -hypothesized that those who develop type 2 are unable to compensate by increasing the amount of insulin secretion by beta cells -this inability to compensate may be one of the genetic factors associated with development of type 2

Autoimmune mediated type 1A DM

-beta cell destruction usually leading to absolute insulin deficiency -autoimmune destruction of pancreas appears to be the primary cause of type 1A dm, when it is not secondary to other diseases -presence of autoantibodies and cytotoxic T cells that target the beta cells, insulin, and some proteins (antigens) on the cells in the pancreatic islets -genetic causes: 18 areas of genome have been ID as being involved, strongest association is with HLA complex, helps body distinguish between self and foreign invaders -environmental causes: a number of environmental agents have been linked to autoimmune destruction of pancreas. Viral infections, Rubella and cytomegalovirus have been implicated as causes. Dietary triggers include cows milk and nitrosamines, increased stress.

Pancreatic Islets

-blood flow thru islets passes from beta cells which predominate in center, to alpha and F cells which are more at periphery -the first cells affected by circulating insulin released from B cells are the Alpha cells, where insulin inhibits glucagon secretion

Glucagon

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

Insulin: inhibits glucose producing pathways

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

Diabetes Mellitus

-group of disorders that have glucose intolerance in common -syndrome characterized by chronic hyperglycemia and other disturbances of carb, fat, protein metabolism

clinical manifestations of type 2

-hyperglycemia -polydipsia -polyphagia, weight loss -fatigue

Insulin

-key player in control of metabolic homeostasis -primary anabolic hormone responsible for limiting blood glucose and fatty acid levels -very short half life ~ 15 minutes -secretion increases in response to increased serum levels of glucose, amino acids, free fatty acids, GI hormones (gastric, secretin, glucagon) that generally occurs after meal, or with parasympathetic stimulation of B-cells -decreases with low serum glucose levels, high levels of insulin or sympathetic stimulation of alpha cells (glucagon, antagonist for insulin)

Effects of glucagon

-major effect of glucagon is to stimulate an increase in blood concentration of glucose -in response to falling serum glucose levels, glucagon has 2 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 pathway by which amino acids are converted to glucose, providing a second source of glucose for the blood

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

Risk factors of type 2 DM

-obesity and inactivity: approximately 90% of individuals who develop type 2 DM are obese. obesity is associated with ten-fold increase in incidence of type 2 DM. Truncal obesity has highest correlation to development of type 2 DM -Age >40 years: type 2 DM generally affects individuals over age 40, although cases have been diagnosed in children as young as two years old. incidence of type 2 DM is rising rapidly among adolescents and young adults -ethnicity: increased incidence among Native Americans, Hispanic/Latino, Pacific Islander, African american populations. -fam. history: 75% concordance rate of type 2 among twins, 95% when it comes to abnormal glucose metabolism. concordance rates for type I much lower. -development of insulin resistance: many complex mechanisms involved in developing insulin resistance

Sulfonylureas

-oral hypoglycemics -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

basal/bolus insulin concept

-quick-acting insulin analogues have absorption profiles that more closely match normal mealtime patterns -can be given immediately before meals, more convenient -quick onset of action matches normal mealtime peaks of plasma insulin better than does human regular insulin -rapid waning of effects of mealtime leads to greater dependency on adequate basal insulin levels between meals and overnight

Diagnostic Criteria

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 (11.1mmol/L) during OGTT OR 4. in a pt with classic symptoms or hyperglycemic crisis, a random plasma glucose >200 mg/dl

limitations of regular insulin

-if given immediately prior to a meal, onset of action is too slow to match 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 insulin needs that occur after eating the meal, patients advised to administer their injection 20-40 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 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 diabetics

clinical consequences of type 1: decreased glucose uptake into cells

-if glucose cannot enter the cells, there is a risk of cell starvation -amino acids uptake into cells also requires insulin -with an insulin deficiency, body can switch to using primarily fatty acids as a fuel source

Patho of 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 secrete more adipokines -adipokines have several normal physiological functions, but when present in high quantities, they stimulate insulin resistance

Patho of type II dm: hyperinsulinemia

-in response to hyperinsulinemia, target cells for insulin 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 -condition is called insulin resistance -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: inhibits catabolic processes

-inhibits catabolic processes -insulin is building hormone, presence of insulin stimulates synthesis of proteins, lipids, carbohydrates and in turn, inhibits catabolic processes -any excess nutrients not metabolized are converted to forms that can be used in other ways or stored for future use

regular insulin

-injectable hypoglycemic drugs -regular insulin is prototype drug -mimics endogenous insulin -this is what they put in the drip at the hospital -original source of insulin was beef or pork, now all insulin is human DNA, reduces allergies and reactions -insulin analogs have been engineered for modified effects, such as rapid onset of action and prolonged duration -"short acting"

Insulin: influences glycogen storage in skeletal muscle

-insulin allows skeletal muscle to import glucose for direct energy supply during activity -like liver, skeletal muscle also stores glycogen b/c these tissues require vast quantities of glucose to make ATP for driving muscle contraction -relative amounts of glucose used for replenishing glycogen stores vs. amount used for energy by muscle depends on level of physical activity during or soon after a meal

Insulin: facilitates intracellular transport of K+

-insulin is 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 and 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

clinical consequences of type 1: fat breakdown in adipose tissue

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

Related Hormones

-pancreatic somatostatin: produced by delta cells and essential in nutrient substrate metabolism (protein, fats, 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

Insulin: facilitates glucose uptake by tissues

-insulin required for facilitated diffusion of glucose into many types of cells, including skeletal muscle -receptor for insulin is embedded in plasma membrane, 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. -only mechanism for cells to take up glucose is by use of glucose transporters (GLUT 4), which are activated by insulin -when insulin concentration is low- GLUT4 transporters present as cytoplasmic vesicles where they are useless for glucose transport -binding of insulin to receptors on such cells leads to rapid fusion of vesicle with the plasma membrane and insertion of glucose transporters, giving cell the ability to take up glucose

clinical consequences of type 2: development of dyslipidemia

-insulin resistance also affects adipose cells. As insulin resistance develops, lipid deposition in adipose tissue decreases and lipolysis activity increases. -insulin resistance occurs for many years prior to diagnosis, for many years, increasing quantities of lipids have been released into plasma -upon diagnosis, most present with dyslipidemia (low HDL, high triglycerides)

Insulin: control of postprandial glucose level

-large % of glucose absorbed from small intestine is immediately taken up by hepatocytes, insulin promotes conversion of glucose to glycogen -main stores of glycogen are in liver, hepatocytes contain between 5-8% glycogen -excess glucose is used for synthesis of triglyceride

clinical consequences of type 1: osmotic diuresis

-of glucose that is filtered in glomerulus, 100% is reabsorbed in proximal convulated tubule. there should no no glucose in urine under normal circumstances. -amount of glucose reabsorbed is limited by the number of carrier molecules in the membrane of the proximal convulated tubule -there is a level at which the carrier molecules become saturated, called tubular maximum, or renal threshold -individuals with diabetes who become hyperglycemic often reach the TM for glucose reabsorption in kidneys -glucose has tendency to attract water because it has high osmotic pressure, any glucose remaining in the filtrate will prevent water from being reabsorbed, thus causing diuresis.

Insulin: stimulates 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 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.

Biguanides

-oral hypoglycemics -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 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 -clients with poor renal function or those with unstable physiologic conditions, lactic acid accumulation can occur. -hypoglycemia can occur

Glargine (Lantus)

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

clinical manifestations of type 1: hyperglycemia

-polyuria: 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 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

goals of insulin therapy

-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 functions

sliding scale: fast acting insulin

-sliding scale used to determine the dosage of insulin based on patient's glucose reading, which should be collected just prior to a meal -sliding scale gives some flexibility, nurse can administer the dose without getting an order

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 -ideal would mimic normal pancreatic basal insulin secretion, provide 24 hour effects, sustain a smooth, peakless insulin profile, ensure reproducible, predicatble effects once steady state is achieved -

Non-immune mediated Type 1B DM

-type 1 DM is less common than autoimmune -most of these cases occur secondary to other diseases such as chronic pancreatitis and CF -chances are higher when there is an attack of pancreas can lead to destruction of beta cells and cause insulin deficiency -type 1B occurs mostly in people of Asian/African descent -affected individuals have varying degrees of insulin deficiency

Patho. of type 2 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

Insulin: increases synthesis from fatty acids

-when liver is saturated with glycogen, additional glucose will be used for fatty acid synthesis -these fatty acids are exported from 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, glycerol and fatty acids are used by adipocytes to make triglyceride -insulin has a fat-sparing effect. it drives the cells to preferentially oxidize carbohydrate instead of fatty acid for energy, and it indirectly stimulates accumulation of fat in adipose tissue

clinical consequences of type 1: decreased potassium uptake into cells

-with an insulin deficiency, potassium isnt being transported into the cell with glucose -increased amounts of K+ remain in the blood, potentially leading to hyperkalemia. hyperkalemia can cause severe complications, including fatal arrhythmias.

Oral hypoglycemics

-work to decrease insulin resistance or to stimulate pancreas to make more insulin -not helpful in type 1 diabetics bc these people dont make any insulin -most OHA's can be heptatoxic, although single agents at usual doses this are not a huge concern -oral hypoglycemics are not effective in managing hyperglycemic emergencies, like ketoacidosis or hyperosmolar coma -any OHA that can cause hypoglycemia has potential to also cause weight gain -most OHA cause some GI distress *CAN ONLY BE GIVEN TO TYPE II*