Diabetes Pathophysiology

What do alpha cells secrete?

glucagon

What does glucaon do?

acts on the liver to release glucose; increases blood glucose

What do beta cells secrete?

insulin

What does insulin do? (broad)

decreases blood glucose; blocks glucagon secretion

What do PP cells secrete?

pancreatic polypeptide

What do pancreatic poltpeptides do?

stimulate gastric and intestinal enzymes; inhibits intestinal motility

What do delta cells secrete?

somatostatin

What does somatostatin do?

stops glucagon and growth hormone; decreases blood glucose

What processes does insulin inhibit?

gluconeogenesis, glycogenolysis, lipolysis, ketogenesis, proteolysis

What processes does insulin induce?

glucose uptake in muscle and adipose tissue, glycolysis, glycogen synthesis, protein synthesis, uptake of ions

What does glucagon do in the liver?

increases glucose production and increases ketone synthesis and protein breakdown

What does glucagon do in the gut?

decreases GLP-1 secretion, causing a decrease in gastric emptying and gut motility

What does glucagon do in the pancreas?

increases insulin secretion, causing a decrease in blood glucose

What does glucagon do in the adipose tissue?

increases lipolysis and decreases TG synthesis

What does glucagon do to the brain?

decreases appetite

What does glucagon do to the heart?

increase inotropic effect and chronotropic effect

What is somatostatin stimulated by?

protein, fat and carbohydrates

What causes pancreatic polypeptides to be released?

hypoglycemia and food (mediated by protein)

When is pancreatic polypeptide frequently increased?

in pancreatic tumors and diabetes

What are the components of the ominous octet?

-impaired insulin secretion from the beta cells

-increased glucagon secretion from the alpha cells

-increased hepatic glucose production from the liver

-neurotransmitter dysfunction in the brain

-decreased glucose uptake in the muscles

-decreased incretin effect in the gut

-increased lipolysis in adipose tissue

-increased glucose reabsorption in the kidney

What is the MOA of glucagon?

major biological role of glucagon is to maintain normal glucose levels during fasting

What is the effect of glucagon?

acts in a catabolic state to oppose the effects of insulin

What role does glucagon have in T2DM?

alpha cells hyper-secrete glucagon → elevated fasting blood glucose

True or False: somatostatin inhibits glucagon secretion

true

True or False: fatty acids and ketones inhibit glucagon secretion

true

What does insulin resistance trigger in the liver?

releasing of more glucose than is actually needed

What is incretin?

secreted by enteroendocrine cells of the large and small intestines

What role does glucagon-like peptide-1 (GLP-1) have?

-augments glucose dependent insulin secretion without causing hypoglycemia

-stimulates insulin gene expression

-inhibits glucagon secretion

-delays gastric emptying

-induces a feeling of satiety

What role does glucose-dependent insulinotropic polypeptide (GIP) have?

-enhances insulin release

-promotes the growth, proliferation, and survival of pancreatic beta cells

-increases glucagon

-lipogenesis

-brain function: leptin resistance; impaired memory

What happens in the kidney without T2DM?

threshold for spilling glucose into the urine is when BG is at least 180

What happens in the kidney with T2DM?

the threshold for spilling glucose in the urine is MUCH higher (~240)

What are the main culprits of insulin resistance in the muscles?

weight gain & inactivity

What hormones normally regulate appetite?

serotonin, dopamine, catecholamines

What is amylin?

co-secreted with insulin; regulates blood glucose by delaying nutrient uptake and suppressing glucagon secretion after meals

What is gastrin?

not well understood but likely controls the secretion of glucagon

What is ghrelin?

stimulates GH secretion, controls appetite, plays a role in the regulation of insulin sensitivity

What is leptin?

controls appetite

What are the components of the insulin resistance cycle?

weight gain, insulin resistance & beta cell failure, decreased GLP1 and decreased appetite control, and increased caloric intake

What happens to insulin and glucagon when glucose is HIGH?

insulin predominates and glucagon is suppressed

What happens to insulin and glucagon when glucose is LOW?

insulin is suppressed and glucagon predominates

What occurs during prolonged fasting?

glycogen stores are depleted; glucagon increases and insulin decreases; gluconeogenesis is sole source of hepatic glucose production

What occurs after a carbohydrate meal?

insulin is stimulated and glucagon suppressed, hepatic glucose production and ketogenesis are suppressed, fat storage occurs in adipose tissue

What occurs after a protein meal?

insulin and glucagon are stimulated, insulin stimulates amino acid uptake and protein formation by muscle, hepatitis glucose output is stimulated by glucagon, which counterbalances any hypoglycemia that insulin might cause

True or False: epinephrine inhibits insulin

true

What happens when fuel delivery to the brain is in jeopardy?

epinephrine, cortisol, and growth hormone stimulate glucagon release

What FBG range can diagnose pre-diabetes?

100-125 mg/dL

What FBG range can diagnose diabetes?

≥ 126 mg/dL

What random blood glucose can diagnose diabetes?

≥ 200 mg/dL + symptoms

What OGTT range can diagnose pre-diabetes?

140-199 mg/dL

What OGTT range can diagnose diabetes?

≥ 200 mg/dL

What A1C can diagnose pre-diabetes?

5.7% - 6.4%

What A1C can diagnose diabetes?

≥ 6.5%

What characterizes type I diabetes?

absolute insulin deficiency

What is the etiology of T1DM?

result of pancreatic beta cell destruction, total deficit of circulating insulin, autoimmune, and idiopathic

What are the autoantibodies present in T1DM?

islet cell antibodies (ICA) and insulin autoantibodies (IAA)

True or False: T1DM has a precipitating event that causes the progressive loss of insulin release

true

What are the clinical manifestations of T1DM?

polydipsia, polyuria, polyphagia, weight loss, fatigue

What characterizes T2DM?

impaired secretion of insulin AND resistance to insulin

What does insulin resistance lead to?

glucose intolerance

What does compensation lead to?

euglycemia

What does beta-cell dysfunction lead to?

imperfect compensation

What two properties leads to T2DM?

insulin resistance + abnormal beta cell function

Which glucose reading gets effected sooner in the progression of T2DM?

postprandial glucose

True or False: beta cell loss over time is linear in T2DM

true

What are the clinical manifestations of T2DM?

recurrent infections & prolonged wound healing, genital pruritis, visual changes, paresthesia, fatigue

What are the risk factors for T2DM?

BMI at least 25 or 23 in asians

inactivity

first degree relative

high risk ethnicity

women who delivered 9 lb baby or GDM

HTN

HLD

PCOS

A1C at least 5.7%

history of CVD

What are the different types of hyperglycemia?

hyperglycemia, DKA, HHNKS

What is glucosuria?

when glucose levels exceed the renal threshold for reabsorption

What are signs of hyperglycemia?

BG >250-300

other altered labs: carbonate, pH, BUN, osmolality, ketones, urine glucose

What are symptoms of hyperglycemia?

polydipsia, polyuria, polyphagia, fatigue, weight changes, blurred vision, dry/itchy skin, recurrent non-healing infections, impotence/ dec. libido, numbness of extremities, bloating

What are the clinical manifestations of hypoglycemia?

cholinergic (sweating, hunger)

adrenergic (tremor, anxiety, palpitations)

neuroglycopenic (fatigue, headache, behavioral changes, confusion, double vision, difficulty speaking, coma)

nocturnal hypoglycemia (night sweats, nightmares, restlessness, morning headaches, lassitude, difficulty awakening)

What are the microvascular chronic complications of T2DM?

retinopathy, nephropathy, and neuropathy

What are the macrovascular chronic complications of T2DM?

cerebrovascular disease, heart disease, peripheral

What is the pathophysiology of retinopathy?

hyperglycemia induced dysregulation of NOS, VEGF and angiogenesis

What are risk factors for retinopathy?

race/ethnicity (black, Hispanic, Asian), pre-existing nephropathy, HTN & dyslipidemia

What are the end organ damages related with retinopathy?

macular ischemia and edema, endothelium leakage, vitreous hemorrhage, retinal detachment, neovascular glaucoma, blindness

True or False: retinopathy is the leading cause of new blindness in US

true

True or False: A1C has no correlation with retinopathy progression

false

What is the leading cause of preventable lower extremity ampuation?

neuropathy

What is the pathophysiology of neuropathy?

hyperglycemia induced polyol accumulation; decreased Na-K-ATPase activity; intra-axonal Na accumulation

What are risk factors for neuropathy?

diabetes severity and duration, smoking & obesity, HTN & dyslipidemia

What are the end organ damages related to neuropathy?

degeneration of myelinated and unmyelinated fibers, neuronal loss, neuropathic pain, and irreversible structural damage

What are polyneuropathies?

manifested clinically by a symmetric sensory loss in the distal lower extremities

How do symptoms of polyneuropathies progress?

begin distally and move proximally; preceded by numbness, tingling, and paresthesia; usually is the feet but can be in the hands

What are examples of autonomic neuropathies?

CV: postural hypotension, exercise intolerance, silent MI

GI: decreased esophageal motility, gastroparesis, delayed gastric emptying, constipation/diarrhea

Genito: neurogenic bladder, urine retention, ED, retrograde ejaculation

sudomotor: anhydrosis, gustatory sweating

What % of dialysis patients are diabetics?

50%

What is the pathophysiology of nephropathy?

hyperglycemia induced formation of AGEs, local RAAS and angiopoietin overexpression

What are the risk factors for nephropathy?

hyperuricemia, family history of kidney disease, pre-existing macrovascular disease or retinopathy, HTN & dyslipidemia

What end organ damages are caused by nephropathy?

functional & structural renal damage, RAAS dysfunction, tubular inflammation, glomerular hypertrophy, mesangial expansion, renal fibrosis, ESRD

What are the stages of T1DM in terms of GFR?

prediabetes, incipient diabetic nephropathy, overt diabetic nephropathy, end stage renal disease

True or False: retinopathy almost always proceeds nephropathy

true

What kinds of stroke occur as macrovascular damage in T2DM?

ischemic!! and hemorrhagic

What CV diseases are associated with the macrovascular damage caused by T2DM?

HTN, Insulin resistance, hypertriglyceridemia, atherosclerosis

What is an example of a peripheral vascular disease that is caused by T2DM?

foot ulcers and infections

What are the risk factors for diabetic foot ulcers?

polyneuropathy, macrovascular and microvascular disease, infections, faulty wound healing

Why are infections common in T2DM?

neutrophil chemotaxis and phagocytosis are defective; cell mediated immunity is also likely abnormal

True or False: diabetics are more prone to infections and may have more severe infections

true

What are common infections faced by T2DM?

candida infections, periodontal disease