Diabetes and Obesity Flashcards
Chemical characteristic stabilizing pro-insulin
Disulfide bonds
When is pro-insulin cleaved to insulin?
During exocytosis
Marker for insulin release
C peptide
What stops a large amount of insulin from reaching systemic circulation?
The pancreas drains into the portal system. There are many insulin receptors in the liver.
Describe the effect of glucose load on post-prandial glucose
No effect; post-prandial glucose is consistent despite different oral glucose loads. Insulin release is what changes.
Non-glycemic activators of insulin release
Incretins (GLP1, GIP), parasympathetic innervation (acetylcholine)
GLP1 full name and effects
Glucagon-like peptide 1; incretin (cAMP-dependent), decreases glucagon secretion, decreases appetite, and delays gastric emptying
GIP full name and effects
Glycagon-dependent insulinotropic polypeptide; incretin
How dos glucose enter the beta cells of the pancreas?
(Bidirectional) GLUT2
How does glucose trigger insulin release from beta cells?
The increased ATP/ADP ratio causes closing of ATP-sensitive K+ channels, causing depolarization. Calcium channels open and the influx causes insulin secretion.
How do catecholamines inhibit insulin release?
By blocking cAMP
What type of receptor is the insulin receptor?
Receptor tyrosine kinase
How does insulin reduce blood glucose?
1) Glucose uptake by insertion of GLUT4 in the membrane of muscle and adipose
2) Glucose usage by glycolysis
3) Glucose storage by glycogen synthesis (via protein kinase B activation of glycogen synthase kinase 3)
4) Promotes fatty acid synthesis
Non-glucose effects of insulin
1) Uptake of amino acids; activation of sodium potassium pump
2) Inhibition of triglyceride breakdown (glucose converted to glycerol backbone and joined with fatty acids from liver to synthesize more triglycerides)
Acanthosis nigricans etiology
Hyperinsulinemia in the context of insulin resistance stimulates the IGF-1 receptor in keratinocytes
Insulin resistance presentation
1) Abnormal glucose metabolism (most common)
2) Acanthosis nigricans
3) Hyperandrogenism (women only)
4) Abdominal obesity
GLP1 comes from the same gene as which protein?
Glucagon (different cleavage sites)
Which hormones inhibit glucagon release?
Insulin and somatostatin
Functions of glucagon
1) glycogenolysis in the liver
2) gluconeogenesis in the liver and kidney
Main source of glucose in post-absorptive state
Glycogenolysis in the liver (followed by gluconeogensis in the liver)
Hypoglycemia presentation
Blood glucose <60 mg/dL; adrenergic symptoms (tremor, palpitations, anxiety, sweating)
Neuroglycopenia presentation
Blood glucose <50 mg/dL; Cognitive impairment, behavioral changes, psychomotor abnormalities, seizure, coma
Type 2 DM diagnostic criteria
One of the following:
- fasting plasma glucose >126 mg/dL
- 2-hour after oral glucose tolerance test >200 mg/dL
HbA1C .6.5%
Glucose profile at A1C of 5%
below 100
Glucose profile at A1C of 6%
120
Glucose profile at A1C of 7%
180
“Triumvirate” of type 1 DM
Beta cell dysfunction, increased hepatic production of glucose, and decreased glucose transport into muscle
How does type 2 dm cause atherosclerosis?
Adipocytes become resistant to the antilipolytic effect of insulin, so plasma free fatty acids increase. THese cause inflammatory and atherosclerotic cytokine production.
Treatment goals for type 2 DM
Reduce complications by lowering A1C to below 7%; manage cardiovascular risk factors
Major cause of death in type 2 DM
Cardiovascular (dyslipidemia)
Effect of intensive glucose control on vascular sequelae of type 2 DM
No effect on macrosvascular/CV mortality; lowers risk of microvascular complications
Autoantibodies in type 1 DM
Islet cell cytoplasm (ICA), islet antigen (IA), glutamic acid decarboxylase (GAD), zinc transporter 8 (ZnT8)
Cause of destruction in type 1 DM
T cell mediated destruction of beta cells; no evidence that autoantibodies are cytotoxic
HLA haplotypes observed in 90% of type 1 DM patients
DR3-DQ2 and DR4-DQ8
Autoimmune polyglandular syndrome type 1 (Whitaker)
Hypoparathyroidism, mucocutaneous candidiasis, adrenal insufficiency (need 2/3) and others
Autoimmune polyglandular syndrome type 2 (Schmidt)
adrenal insufficiency, type 1 DM, autoimmune thyroid disorder (need 2/3) and others
Perinatal factors implicated in type 1 DM
maternal age and birth order (higher risk in first born)
Type 1 DM presentation
Lack of insulin production, polyuria, polydipsia, weight loss, DKA, perineal candidiasis, cataracts
Mechanism of hyperglycemia in DKA
Insulin deficiency allows glucagon to stimulate glucagon production by the liver, unchecked. Severe hyperglycemia leads to osmotic diuresis and volume depletion.
Mechanism of ketoacidosis in DKA
Increased release of free fatty acids and their subsequent oxidation bu the liver generates ketone bodies. These cannot be cleared effectively by the kidney due to volume depletion
DKA signs/symptoms
Nausea/vomiting, hypothermia, tachycardia, Kussmaul breathing, ileus, acetone breath, AMS
DKA lab tests
Rothera’s test (alkaline urine turns bright red when nitroprusside tablets are added); direct measurement of serum bea-hydroxybutarate; anion gap metabolic acidosis; hyperosmolality; elevated triglycerides
DKA treatment
Replace fluids, insulin for hyperglycemia, replace electrolytes
Hyperosmotic hyperglycemic nonketotic state
DKA-like but without ketoacidosis; risk of coma, AMS
Metformin class
Biguanides
Metformin- MOA
activates AMP kinase, leading to increased skeletal muscle glucose uptake and decreased hepatic gluconeogenesis by improving hepatic insulin sensitivity
Metformin- ADRs
diarrhea, nausea, abdominal pain, B12 deficiency, “risk of lactic acidosis” (from old biguanides). May cause weight loss.
Metformin- clearance
Renal
Metformin- contraindications
Renal dysfunction, liver dysfunction, acidosis
Thiazolidinediones- MOA
Decreases level of free fatty acids via PPARγ, reducing FFA mobilization. This indirectly causes increased uptake of glucose and improved hepatic insulin sensitivity
Thiazolidinediones- examples
Pioglitazone, rosiglitazone
Thiazolidinediones- ADRs
lower extremiety edema, CHF exacerbation, weight gain (FFAs), decreased bone density, myocardial infarction (rosiglitazone), bladder cancer (pioglitazone)
Secretagogues- MOA
Bind to sulfonylurea receptor 1 (SUR1), a subunit of the potassium channel on beta cells. This causes depolarization and increases insulin exocytosis.
Secretagogues- examples
Sulfonylureas: glipizide, glyburide, glimepiride (2nd generation drugs);
Meglitinides: repaglinide, nateglinide, mitiglinide
Secretagogues- ADRs
Hypoglycemia, weight gain (sulfonylureas), CV disease (sulfonylyreas, via SUR2)
DPP4 inhibitors- MOA
Slow degradation of GIP and GLP1 by DPP4
DPP4 inhibitors- examples
Sitaglipin, linagliptin, alogliptin, saxagliptin
DPP4 inhibitors- ADRs
nausea, headache, possibly pancreatitis;
reduce dose in CKD
DPP4 inhibitors- metabolism
Renal clearance (except linagliptin which is cleared by the gut)
GLP1 agonists- MOA
GLP1 analog that is resistant to DPP4 degradation
GLP1 agonists- examples
Exenatide, liraglutide, dulaglutide, albiglutide
GLP1 agonists- ADRs
Nausea, diarrhea, constipation. May cause weight loss.
GLP1 agonists- contraindications
Thyroid C-cell hyperplasia, pancreatitis, personal/family history of medullary thryoid cancer. Reduce dose if CKD.
A-glucosidase inhibitors- MOA
Inhibits enzymatic breakdown of carbs intomonosaccaride units by pancreatic alpha-amylase and intestinal alpha-glucosidase hydrolase enzymes at the brush border. Sugars bypass small intestine and are delivered to the colon where absorption is slower.
A-glucosidase inhibitors- examples
Acarbose, miglitol
A-glucosidase inhibitors- metabolism
Acarbose is cleared by the gut and kidney. Miglitol is cleared by the kidney only.
A-glucosidase inhibitors- ADRs
Diarrhea, flatulence, bloating, abdominal pain
A-glucosidease inhibitors- contraindications
Liver disease, IBD, renal disease. Watch LFTs.
SGLT2 inhibitors- MOA
Stop glucose reabsorption by the kidney in the PCT
SGLT2 inhibitors- examples
Canaliflozin, dapagliflozin, empagliflozin
SGLT2 inhibitors- ADRs
polyuria, UTI, vulvovaginal candidiasis, dehydration, hypotension
SGLT2 inhibitors- metabolism
Cleared by gut and kidney
SGLT2 inhibitors- contraindications
CKD
Amylinomimetics- MOA
Amylin analog that binds to brain nuclei to increase satiety, decrease appetite, slow gastric emptying, and suppress glucagon
Amylinomimetics- examples
Pramlinitide
Amylinomimetics- ADRs
Nausea
Deposits found in pancreatic islet beta cells in patients with type 2 DM
Islet amyloid polypeptide (IAPP, or amylin)
Bile acid sequestrants- examples
Colesevalam
Bile acid sequestrants- ADRs
GI
D2R agonists- MOA (diabetes)
Given 2 hours after waking and may create a circadian peak in DA tone, which may result in increased insulin sensitivity
D2R agonists- examples
Bromocriptine
D2R agonists- ADRs
Nausea, headache
D2R agonists- contraindications
pregnant/nursing
Basal (long-acting) insulins
Glargine, detemir
Intermediate-acting insulin
Neural protamine Hagedorn (NPH; used as basal insulin)
Bolus (rapid-acting) insulins
Lispro, Aspart, Glulisine
Regular insulin (short-acting) use and dosing
Useful for grazing eating pattern or in patients with tube feeding/peritoneal dialysis. Dosed every 6-8 hours.
Type of basal insulin in combination insulin preparations
Neural protamine Hagedorn (NPH)
What might prolong the effects of insulin?
Kidney disease
Mechanisms for hyperglycemia-induced damage
1) overproduction of superoxide (ROS) by mitochondrial ETC
2) Intracellular production and accumulation of advanced glycosylated end products (AGEs), which diffuse out to modify extracellular molecules, bind the receptor for AGE (RAGE), and trigger inflammatory cytokines and growth factors
3) Activation of protein kinase C, leading to vascular damage
3) Acceleration of the aldose reductase (Polyol) pathway, which generates sorbitol and then fructose from glucose. This consumes NADPH and decreases glutathione, exacerbating ROS damage.
4) Increased hexosamine pathway activity, which generats UDP N-acetyl glucosamine. This is bad for vessels.
Mechanism of microvascular damage in diabetes
Hypercglycemia causes diffuse thickening of basement membranes, leading to distortion and eventual occlusion of capillaries.
Diabetic retinopathy- presentation
Intraretinal hemorrhages, cotton wool spots, hard exudates, microvascular abnormalities (microaneurysms, tortuous vessels, occluded vessels). New blood vessels if proliferative. Macular edema may occur in proliferative retinopathy.
Diabetic retinopathy- treatment
If macular edema is present, use VEGF imhibitors (bevacizumab, ranibizumab, aflibercept); panretinal photocoagularion in proliferative retinopathy
Diabetic nephropathy- presentation
Persistent albuminuria; mesangial expansion, glomerular BM thickening, podocyte injury, glomerular sclerosis (Kimmelstiel-Wilson lesion), decreased GFR
Diabetic neuropathy-presentation
Distal symmetric polyneuropathy (usually sensory), autonomic neuropathy, polyradiculopathies, mononeuropathies (CNIII, median nerve), acute painful neuropathies (treatment-induced)
Diabetic neuropathy- treatment
Antidepressants (duloxetine, amitriptyline), topical anasthetics (capsaicin, lidocaine), anticonvulsants (pregablin), footcare
Mechanism of marcrovascular complications in diabetes
Overproduction of VLDL in type 2 DM; slower clearance of TG-rich lipoproteins; enzymatic exchange of T from VLDL with cholesterol ester from LDL, leading to TG-rich LDL. TG-rich LDL is the preferred substrate for hepatic lipase, yielding small dense LDL. sdLDL are atherogenic.
Non-vascular diabetes complications
Diabetic cheiroarthropathy, Dupuytren’s contracture, increased infection susceptibility, toenail onychomycosis, necrobiosis lipoidica, foot problems
What is adiponectin?
A protein hormone secreted by adipose cells. It is benficial and anti-inflammatory. Associated with weight loss.
From where is ghrelin secreted?
Fundus of the stomach
Ghrelin functions
Orexigenic; signals to hippocampal area, hedonic system, and homeostatic brain. Secreated at meal suppression.
Ghrelin dysfunction in obesity
Levels are low in the fasting state but are NOT suppressed after eating as they should be
How does GLP-1 promote satiety?
Inhibits orexigenic neuropeptide Y
“Hunger center” of the hypothalamus
Lateral hypothalamus
“Satiety center” of the hypothalamus
Ventromedial hypothalamus
How does leptin promote satiety?
Acts in the arcuate nucleus and stimulates POMC production. THis increases alpha-melanocyte stimulating hormone (aMSH), which acts on MC4-R and MC3-R, causing appetite suppression.
How does ghrelin promote hunger?
Ghrelin acts on arcute nucleus to increase release of agouti-related peptide, which inhibits MC4-R and stimulates the orexigenic pathway.
Serotonin (5HT2C) agonist anti-obesity medications
Lorcaserin, sibutramine, dexfenfluramine
Naltrexone- MOA
Acts on mu receptors
Liraglutide (and Rimonabont)- MOA
GLP-1 agonist
Topamax- MOA
Potentiates GABAergic neurons
Bupropion
Dopamine agonist
Phentermine- MOA
Inhibits sodium-dependent norepinephrine transportor, reducing NE uptake, as well as serotonin and DA uptake.
Phentermine- ADRs
Dry mouth, constipation, insomnia, palpitations, headache, irritability
Phentermine- contraindications
Active CV disease, HTN, cardiac arrhythmias, hyperthyroidism, glaucoma
