Pathophysiology of Diabetes Mellitus Diabetes = Hyperglycemia, which is defined as: --fasting plasma glucose above 126 mg dl --oral glucose

tolerance test !"#$$% above 2&& mg dl 're-Diabetes is defined as: --impaired fasting glucose !()#% of 1&&-12* mg dl --impaired glucose tolerance !(#$% of 1+&-1,, mg dl Acute Complications of Uncontrolled Diabetes !all directly caused by hyperglycemia% --'olydypsia due to plasma glucose hyperosmolarity --'olyuria due to e-cess fluid inta.e and glucose-induced osmotic diuresis --/eight loss due to calories lost as glucosuria, leaving a negative calorie balance --'olyphagia due to glucosuria and negative calorie balance --'oor wound healing, gingivitis, blurred vision

Chronic Complications of Uncontrolled Diabetes

0hronic complications may be due to mitochondrial supero-ide overproduction in response to hyperglycemia1

2acrovascular Atherosclerosis: diabetics have a high incidence of coronary, cerebral, and peripheral artery diseases1 0aused by dyslipidemias including elevated 3D3 and triglycerides, low HD3, and reduced fibrinolytic activity1 2anagement includes foot care1 2icrovascular Diseases of Diabetes 11 Diabetic Retinopathy has many manifestations, including microaneurysms, microhemorrhages, proliferative vessel changes, and vitreous bleeds !cause blindness%1 Diabetic retinopathy is caused by basement membrane deterioration and ischemia1 21 Nephropathy progresses from microalbuminuria to proteinuria to uremia to 456D1 7ephropathy is caused by hyperfiltration, increased glomerular pressure, and 82 thic.ening1 91 Neuropathy can be peripheral !symmetrical stoc.ing-glove numbness tingling%, autonomic !erectile dysfuntion, enteropathy, gastroparesis, orthostatic hypotension%, or mononeuropathic !single nerve pain palsy%1 'eripheral and autonomic neuropathies are caused by metabolic schwann cell defects and axonal degeneration1 2ononeuropathies are caused by ischemia, and resolve on their own within a year1

The Diabetic Foot $his is a combination of 'eripheral 7europathy !leads to undetected trauma, blisters, ulcers% and 'eripheral :ascular Disease !impairs healing, allows infection%1

Endstage Complications of Uncontrolled Diabetes 11 Diabetic Ketoacidosis results from complete lack of insulin and reliance on fatty acids for energy1 $here is unrestrained lipolysis and .etone synthesis, causing acidosis and .etonemia1 'atients will show Kussmaul respiration1 $his is a medical emergency1 21 Non-Ketotic Hyperosmolarity is an extreme hyperglycemia without acidosis1 (t is caused by insufficient insulin resulting in poor glucose upta.e and increased hepatic glucose output1 $here is ;ust enough insulin to suppress .etone synthesis1 $he e-treme hyperglycemia leads to osmotic diuresis and vascular collapse1 Diabetic Control 11 5elf-monitoring of blood glucose 21 Hemoglobin <1c !=glycohemoglobin>% monitoring measures glycemia over the last 2-9 months1 Hemoglobin <1c ? @ is good1 Hemoglobin <1c A , is bad1 Type 1 Diabetes Mellitus 0haracteriBed by 8eta cell deficiency, leading to complete insulin deficiency1 $his leads to severe metabolic lability and ketoacidosis1 2etabolic lability is hard to treat1 D2 type 1 is almost always an autoimmune disease caused by anti-islet, anti-#<D, or anti-insulin antibodies1 $hese cause lymphocytic inflitration and destruction of the pancreas islets1 <lthough the destruction is gradual, the clinical onset is usually acute1 D2 type 1 is associated with other autoimmune conditions including vitiligo and hypothyroidism1 D2 type 1 usually occurs in people ?9* yo who are of thin-to-normal body weight1 (t is much less common than D2 type 2, and shows some H3< associations1 amily history is rare1 D2 type 1 always reCuires insulin therapy, and will not respond to insulin-stimulating oral drugs1 6emember that metabolic lability and glucose swings are a hallmar. of D2 type 11 D4nd-stage D2 type 1 is ketoacidosis1 Type 2 Diabetes Mellitus 0haracteriBed by insulin resistance and relative! not complete insulin deficiency1 D2 type 2 is caused by "eta cell deficiency coupled with peripheral insulin resistance1 --'eripheral insulin resistance is the hallmar. of D2 type 21 <lthough insulin levels may be high, this does not cause hypoglycemia1 $his is due to receptor density and post-receptor changes in response to chronic hyperinsulinemia1 --"besity is the main cause of insulin resistance1 --8eta cell deficiency occurs over years as islets fail from insulin overproduction1 (nsulin levels become inadeCuate to overcome the peripheral resistance1 D2 type 2 develops when insulin production can no longer overcome peripheral insulin resistance1 'atients become unresponsive to insulin-stimulating oral drugs, and ultimately reCuire insulin in;ections1 8ut because there is always some residual insulin secretion, there is little metabolic lability and glucose levels tend to stay stable1 D2 type 2 usually occurs in people A9* yo who are obese1 amily history is very common! and twin concordance is extremely high1 D4nd-stage D2 type 2 is Non-Ketotic Hyperosmolarity1

4tiology )ormerly .nown as <ge of onset "besity )amily History $win concordance H3< association Fetosis (nsulin resistance 4ndogenous insulin 6espond to "ral <gents 2etabolic lability

Type 1 Diabetes <utoimmune (DD2 Eounger 6are 6are Ees Ees 7o 7o 7o 3abile

Type 2 Diabetes 'eripheral resistance 7(DD2 or =adult onset> diabetes "lder 0ommon 0ommon 7o 7o Ees Ees Ees 7ot labile

!6aymond removed image of natural history of type 2 diabetes: glucose levels, insulin resistance and secretion1%

ther causes of hyperglycemia 11 #estational diabetes is caused by excess counter-insulin hormones of pregnancy, which lead to insulin resistance1 $he resulting maternal hyperglycemia is transmitted to the fetus, causing fetal pancreatic hypertrophy1 $he baby will be large and fat, with neonatal complications1 21 Defective insulin receptors or post-receptor signal transduction1 91 =#lucose to-icity> in which hyperglycemia itself causes more insulin resistance1 $his is a feedforward cycle that leads to .etoacidosis and severe hyperglycemia1

Carbohydrate Metabolism and !ypoglycemia (ncreased blood glucose stimulates insulin secretion1 High insulin will promote glucose upta.e, glycolysis, and glycogenesis, as well as upta.e and synthesis of amino acids, proteins, and fat1 3ow insulin will promote gluconeogenesis, glycogenolysis, lipolysis, and proteolysis1 !igh insulin "o$ insulin "i#er #lycolysis #lycogenesis #luconeogenesis #lycogenolysis Adipose Tissue $riglyceride synthesis 3ipolysis Muscle <mino acid upta.e 'rotein synthesis 'roteolysis

%ormal &esponses to Eating and Fasting 11 0H" fed state: increased insulin secretion, causing glycolysis, glycogen storage, fatty acid synthesis storage, and protein synthesis1 21 "vernight fast: low insulin and high glucagon cause glycogen brea.down, hepatic gluconeogenesis, and lipolysis1 91 'rolonged fast: e-tremely low insulin and low glucagon cause lipolysis to ta.e over1 3ipids are the main fuel source1 #luconeogenesis is minimiBed, as it causes nitrogen wasting, ammonia build-up, and loss of muscle mass1 Counter'&egulatory !ormones $he following hormones raise blood glucose and oppose insulin: --#lucagon --4pinephrine 7orepinephrine --0ortisol --#rowth Hormone $hese are =fight or flight> hormones that raise glucose to fuel muscles1 $hey cause an-iety, alertness, apprehension, sweating, and tachycardia1 $hese hormones are released due to stress1 $herefore, stress worsens diabetic control, raises blood glucose, and generally worsens diabetes1 !ypoglycemia Hypoglycemia is defined by =#hipple$s %riad>: 11 Documented low plasma glucose 21 5ymptoms of hypoglycemia 91 6esponse to administered carbohydrate $here are two classes of hypoglycemic symptoms: 11 Adrenergic symptoms due to catecholamine release and counter-regulatory hormones1 $hese symptoms include tremor, blurred vision, wea.ness, palpitations, an-iety, emotional lability, headache1 <drenergic symptoms mildly dangerous1 21 Neuroglucopenic symptoms due to inadeCuate glucose to the brain1 $hese symptoms include confusion, slurred speech, sieBures, somnolence, and coma1 :ery dangerous1 &eacti#e #ersus Fasting !ypoglycemia

(t is not normal to become symptomatically hypoglycemic, even during a prolonged fastG Reactive&postprandial Hypoglycemia occurs a few hours after a meal1 (t is common, and not associated with disease1 2ay be caused by overly rapid gastric emptying !=alimentary hypoglycemia>%1 asting Hypoglycemia occurs post-absorptively !A1& hours after a meal%1 (t is abnormal, and is usually caused by excess insulin1 $his may be e-ogenous insulin !over-in;ection during diabetes therapy% or endogenous insulin !insulinoma%1 (nsulinomas may be detected by putting patients on a prolonged fast and loo.ing for persistently high insulin levels or symptoms of hypoglycemia1 "ther causes of fasting hypoglycemia include defective gluconeogenesis !liver failure, alcoholic hypoglycemia% and counter-regulatory hormone deficiency !adrenal insufficiency%1