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HMS Homeostasis II > Diabetes III - Obesity and Diabetes Complications > Flashcards

Diabetes III - Obesity and Diabetes Complications Flashcards

1
Q

Categories of end-organ complications in diabetes mellitus

A
  • Glucose related
  • Vascular related
  • Other endocrinologic or metabolic complications
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2
Q

Glucose-related DM complications

A
  • Sorbitol: In the setting of hyperglycemia, intracellular glucose is increased. Excess intracellular glucose is diverted to an alternate pathway, leading to an accumulation of sorbitol. The subsequent osmotic gradient draws water into tissue
  • Advanced glycation end products: AGEs damage the basement membrane of the extracellular matrix and increase procoagulant activity, vascular permeability, and monocyte influx (a factor in development of atherosclerosis) that contribute to vascular injury
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3
Q

Vascular-related DM complications

A

Abnormalities in the endothelium and supporting cells, leading to an increase in vascular permeability.

This may be caused by local hemodynamic or inflammatory factors, such as cytokines (including IL-1), nitric oxide, growth factors (including vascular endothelial growth factor (VEGF)), and angiotensin II.

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4
Q

Other endocrinologic or metabolic complications

A
  • Abnormalities in platelet function and growth factors
  • Associated lipid abnormalities (high triglycerides and low HDL seen in insulin resistance)
  • Hyperinsulinemia, leading to endothelial dysfunction and a prothrombotic state
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5
Q

Diabetic retinopathy

A
  • May result from macular edema, hemorrhage from retinal vessels, retinal detachment, or glaucoma
  • Most asymptomatic, however progression may be rapid if untreated.
  • Direct relationship between degree of hyperylgycemia and risk of development
  • Hyperglycemia leads to pericyte death and basement membrane thickening, resulting in increased permeability and local edema.
  • Bleeding can lead to fibrosis and traction on the retina, which can cause retinal detachment.
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6
Q

Retinal neuropathy in type I vs type II diabetes

A
  • Happens to 50-80% of type II, virtually all of type I
  • Progression depends on duration and control of diabetes
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7
Q

Normal vs Diabetic retina on exam

A
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8
Q

Diabetic neuropathy may be classified into. . .

A

. . . Nonproliferative or proliferative.

Based on the absence of presence of neovascularization within the retina.

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9
Q

Diagnosing diabetic retinopathy

A
  • Consistent history
  • Dilated fundoscopic exam
  • Digital stereoscopic retinal imaging
  • Fluorescein angiography (to detect neovascularization)
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10
Q

Treating diabetic retinopathy

A
  • Glycemic control and blood pressure control can decrease both the incidence and progression of diabetic retinopathy.
  • Laser photocoagulation of new proliferative retinal blood vessels can decrease vision loss
  • Intravitreal anti-VEGF injections, intravitreal steroid injections, and vitrectomy are more invasive treatments that can also be used.
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11
Q

Pathogenesis of diabetic nephropathy

A
  • AGE’s can lead to irregular thickening of the glomerular basement membrane. In order to maintain filtration, pressure within the glomeruli increases, leading to enlargement of the glomeruli.
  • Higher glomerular pressures lead to hyperfiltration, such that glomerular filtration rates can initially increase.
  • Over time, however, increased glomerular pressures can lead to podocyte damage and development of albuminuria
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12
Q

Diabetic nephropathy strongly increases the risk of ___, even relative to other diabetes patients.

A

Diabetic nephropathy strongly increases the risk of severe cardiovascular disease, even relative to other diabetes patients.

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13
Q

Diagnosing diabetic nephropathy

A
  • Urine albumin-to-creatine ratio screening: Screening tests for urine albumin should begin at 5 years after diagnosis of type 1 diabetes and at the time of diagnosis of type 2 diabetes.
  • Kidney biopsy: Rarely indicated unless an additional diagnosis is possible that would require additional therapy. Changes include mesangial expansion, GBM thickening, afferent/efferent arteriosclerosis, glomerular hypertrophy, and Kimmelstiel-Wilson nodules.
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14
Q

Treating diabetic nephropathy

A
  • Blood pressure control: RAAS inhibitors work both systemically and locally, and so are doubly beneficial. The risk, of course, is reduced GFR
  • Glycemic control
  • Smoking cessation
  • Note that these can only prevent further damage, but cannot restore kidney function. Ultimately, if GFR falls low enough to be incompatible with life, dialysis or transplant are necessary.
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15
Q

Diabetic neuropathy mechanisms

A
  1. The metabolic mechanism, whereby elevated sorbitol in neurons exposed to hyperglycemia leads to nerve dysfunction and damage.
  2. The vascular mechanism, whereby vascular damage leads to ischemia which in turn causes nerve dysfunction and damage.
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16
Q

Symmetric sensorimotor neuropathy in diabetes

A
  • Most common form of diabetic neuropathy
  • Altered sensitivity to vibration and heat (leading to loss of sensory perception). This can manifest symptomatically as paresthesias (including numbness and/or pins and needles sensation), hyperalgesia, and allodynia.
  • Longer nerve fibers are damaged first since they are the longest and most susceptible to injury (hence, neurons that innervate the toes/feet often go first).
  • Decreased or absent reflexes
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17
Q

Autonomic neuropathy in diabetes

A
  • Gastric/intestinal dysmotility (diarrhea or constipation, altered absorption, bloating, early satiety)
  • Erectile dysfunction
  • Bladder dysfunction
  • Cardiac dysfunction (loss in variation in heart rate and vascular tone, resting tachycardia, postural hypotension)
  • Changes in vascular tone
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18
Q

Acute mononeuropathies in diabetes

A
  • Acute onset
  • Involve a single nerve
  • Lead to pain but with recovery typically within 6-12 weeks
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19
Q

Cranial and peripheral motor neuropathy in diabetes

A

self explanatory

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20
Q

Treatment of diabetic neuropathy

A
  • Glycemic control
  • Management of neuropathic pain (ex, pregabalin, a gaba analogue used in treating fibromyalgia)
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21
Q

Severe peripheral vascular disease in diabetes may lead to . . .

A

. . . gangrenous extremities and amputations

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22
Q

Foot ulcers in diabetes mellitus

A
  1. Loss of protective sensation in the feet (peripheral neuropathy) leading to an increase in foot trauma
  2. Poor blood flow (peripheral vascular disease)
  3. Predisposition for infections results in an increased risk for development of ulcers and subsequently amputations.
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23
Q

Musculoskeletal complications in diabetes mellitus

A
  • Dupuytren’s contractures: A proliferation of connective tissue in the hand and thickening of the skin, leading to decreased mobility of the fingers.
  • Charcot joint: A degenerative condition seen in weight-bearing joints characterized by bone destruction and deformity.
  • Carpal tunnel syndrome
  • Association between diabetes and osteoarthritis, gout, and osteoporosis, though the mechanisms remain unclear.
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24
Q

BMI

A

BMI = weight / height2

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25
Q

BMI categories according to WHO standard

A
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26
Q

Waist circumference

A
  • Measured in a horizontal plane just above the iliac crests, parallel to the ground, at the end of a normal expiration
  • A waist circumference >35 inches (88 cm) in women and >40 inches (102 cm) in men is associated with increased morbidity
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27
Q

Heritability of obesity

A

~40-70%

Thus, genetics play a substantial role in the development of obesity, but of course they are informed by diet, microbiome, sleep habits, and endocrinological disease.

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28
Q
A
29
Q

Lipostat or Adipostat

A

Proposed names for the body’s apparent “set point” for bodyweight, regulated by the hypothalamus, to which the body tends to return to following interventions or changes in diet.

30
Q

POMC/CART neurons

A
  • Aka POMC (proopiomelanocortin) and CART (cocaine- and amphetamineregulated transcript) neurons
  • Activate neural pathways that increase energy expenditure and promote weight loss, through the production of signaling molecules such as α-MSH
  • α-MSH binds to the melanocortin receptor and reduces food intake. This is called an anorexigenic effect.
  • Mutations in the gene encoding MC4R are found in 4- 5% of patients with severe obesity
31
Q

NPY and AgRP neurons

A
  • NPY (neuropeptide Y) and AgRP (agouti-related peptide) neurons
  • NPY/AgRP neurons activate neural pathways that promote food intake. This is called an orexigenic effect.
32
Q

GI tract hormones that regulate hunger and satiety

A
  • Insulin: From pancreas. Promotes satiety
  • Ghrelin: From stomach. Stimulates appetite and promotes food intake, most likely by stimulating the NPY/AgRP neurons in the hypothalamus.
  • Peptide YY: From ileum and colon. Released in response to consumption. It decreases appetite and signals satiety, presumably by stimulating POMC/CART neurons in the hypothalamus. PYY also decreases the rate of gastric emptying and decreases intestinal motility, which contribute to satiety
33
Q

Adipocyte hormones that regulate hunger and satiety

A
  • Leptin: A key hormone produced by adipocytes that indicates energy stores in fat. Promotes satiety.
  • Adiponectin: Hormone produced by adipocytes that has anti-diabetic, antiinflammatory, anti-atherogenic, and cardioprotective effects. Promotes insulin sensitivity and negatively regulates ectopic fat storage. Adiponectin levels are reduced in obesity.
34
Q

Leptin production

A

Leptin is produced by adipose tissue in proportion to triglyceride stores. Higher adipose tissue stores lead to increased leptin secretion and higher circulating levels of leptin.

35
Q

Neurohormonal signals regulating hunger and satiety

A
36
Q

Ob/Ob mice vs Db/Db mice

A

Douglas Coleman proposed that ob/ob mice were deficient in a “circulating satiety factor” that regulates feeding and weight. In contrast, db/db mice overproduced the circulating satiety factor but could not respond to it (perhaps due to a defective receptor or resistance to the factor).

It is now known that Coleman was correct, and this circulating factor is Leptin.

37
Q

Neurochemical role of Leptin

A

Leptin crosses the blood-brain barrier and acts in the hypothalamus to stimulate the anorexigenic POMC/CART neurons and inhibit the orexigenic NPY/AgRP neurons, leading to reduced food intake.

When adipose tissue stores are low, leptin levels decrease, leading to increased food intake. Leptin also acts through the hypothalamus to stimulate energy expenditure, physical activity, and thermogenesis. Thus, overall, leptin has anorexigenic and catabolic effects.

38
Q

Why is leptin not useful in treating most cases of obesity?

A

Because most cases of obesity are due to leptin resistance. These individuals already have sky high leptin levels!

In other words, in obesity, the anorexigenic effect of leptin appears to be blunted despite high leptin levels. This remains an area of active research.

39
Q

The low-adiposity state and its treatment

A
  • Commonly seen secondary to anorexia nervosa
  • Individuals may develop secondary hypogonadism and infertility
  • In women, this my manifest as amenorrhea
  • Thus, leptin has a role in regulating gonads by acting as a signal that the body is not in a state of starvation
  • While administration of physiologic doses of leptin to these individuals can restore gonadal function, it also causes additional weight loss, which can be counterproductive as they are already low or relatively low weight
  • Therefore, normalizing of caloric intake, caloric expenditure, and adipocyte mass is the most appropriate treatment modality for this condition.
40
Q

Endocrinologic changes in the starvation state

A
  • Secondary hypogonadism (leptin regulated)
  • Growth hormone suppression
  • Sick euthyroid syndrome
41
Q

Blood pressure and BMI

A

A linear relationship exists between blood pressure and BMI

42
Q

Obesity hypoventilation syndrome

A

Characterized by a decreased response to hypoxia (abnormally low O2 levels in the blood) and hypercapnia (abnormally high CO2 levels in the blood).

The main symptom of OHS is daytime hypersomnolence. OHS is associated with sleep apnea, polycythemia, and right-sided heart failure.

Note: This is a separate phenomenon from obesity-related restrictive lung disease! Though, they often co-occur.

43
Q

Non-alcoholic fatty liver disease

A

Obesity and accompanying insulin resistance increase mobilization of free fatty acids from adipose tissue, which are taken up by and accumulate in hepatocytes, resulting in NAFLD.

NAFLD can progress to nonalcoholic steatohepatitisand eventually to cirrhosis.

44
Q

Broad pathophysiologic pathways in Obesity

A
45
Q

Treating obesity

A
  • Decreased caloric intake, increasing physical activity
  • Lifestyle interventions the foundation of treatment
  • Moderate weight loss, defined as a 5-10% reduction in baseline weight, is associated with clinically meaningful improvements in cardiometabolic risk and overall morbidity
  • Cognitive behavioral therapy
  • Pharmacologic appetite suppressors and inhibitors of intestinal absorption
  • Surgical removal of fat
46
Q

Caloric energy deficit sufficient for weight loss

A

500-750 kcal/day

Generally, this translates to a caloric intake of 1,200- 1,500 kcal/day for women and 1,500-1,800 kcal/day for men

47
Q

A note on diet composition and weight loss

A

Multiple randomized trials comparing diets with different macronutrient composition (such as low carbohydrate (like Atkins), low fat, and Mediterranean diets) have shown that weight loss is achievable with caloric reduction regardless of the diet composition.

A major factor in successful weight loss is the degree of adherence to the diet, irrespective of the specific macronutrient composition.

48
Q

Cognitive behavioral therapy in treating obesity

A
  • Self-monitoring of diet and physical activity (many patients use smartphone apps for this)
  • Regularly monitoring weight on a scale, measuring food, and recording physical activity
  • Stress management
  • Stimulus control (e.g., using smaller plates and avoiding triggers for eating unhealthy food).
49
Q

Who is a candidate for pharmacologic weight loss therapies?

A

Candidates for drug therapy include any individual with a BMI ≥30 kg/m2, or BMI ≥27 kg/m2 and concomitant obesity-related disease, for whom lifestyle interventions have not been successful in meeting weight loss goals.

50
Q

What to expect when perscribing a pharmacologic weight loss therapy

A
  • Ideally, weight loss medications should be prescribed in conjunction with participation in a lifestyle program, as this combination can help increase and maintain weight loss
  • In controlled studies, weight loss medications are generally associated with 3-9% weight loss from baseline at 3- 12 months
  • Of note, most patients regain weight when weight loss medications are stopped
  • In most cases, if weight loss of 5% from baseline is not achieved after 3 months of treatment with a weight loss medication, discontinuing the weight loss medication is recommended.
51
Q

Orlistat

A

Main FDA-approved weight loss medication that acts by decreasing intestinal fat absorption.

Orlistat is a pancreatic lipase inhibitor, which decreases hydrolysis of dietary fat and thus inhibits GI fat absorption. So, obviously, the main side effect of this is going to be steatorrhea, which is not pleasant for patients.

52
Q

Pharmacologic appetite suppressor summary

A
53
Q

Bariatric surgery

A
  • The single most effective treatment for significant and sustainable weight loss in individuals with obesity
  • Results in weight loss of ~15-30% of baseline weight and is associated with marked improvements in type 2 diabetes, hypertension, cardiovascular risk, and numerous obesity-related comorbidities.
  • Remission of type 2 diabetes and hypertension may occur with weight loss after bariatric surgery
54
Q

Mechanisms of weight loss following bariatric surgery

A
  • Restriction: Reducing the stomach’s capacity to hold food, leading to earlier satiety and decreased calorie intake. Achieved by placing a gastric band laporoscopically (lap band) or by sleeve gastrectomy.
  • Malabsorption: Reducing the amount of nutrient absorption in the small intestine. Achieved by bypassing a portion of the SI or by diverting biliopancreatic secretions required for nutrient absorption.
55
Q

Main bariatric surgical procedure summary

A
56
Q

Anatomy of main bariatric surgical procedures

A
57
Q

Complications of bariatric surgery

A
  • Leaks at anastomoses and staple lines
  • Marginal ulcers (at sites of anastamosis)
  • GERD
  • Vitamin and micronutrient deficiencies (hence supplementation of vitamin B12, vitamin D, folic acid, iron, and calcium is recommended)
  • Early dumping syndrome
  • Late dumping syndrome (aka postprandial hyperinsulinemic hypoglycemia)
  • Cholelithiasis (hence Ursodiol is given prophylactically following surgery)
  • Nephrolithiasis
58
Q

Early dumping syndrome

A
  • Clinical syndrome: Abdominal pain, diarrhea, nausea, and tachycardia, typically within 15 minutes of food intake
  • Pathophysiology: RYGB results in rapid emptying of ingested food into the small intestine. The hyperosmolality of the food results in rapid fluid shifts from the plasma into the bowel, causing hypotension and triggering the sympathetic nervous system. This is worsened by foods high in simple sugars
  • Treatment: Dietary and behavioral modification, including avoiding simple sugars, consuming foods high in fiber and complex carbohydrates, and eating smaller frequent meals.
59
Q

Late dumping syndrome

A
  • aka postprandial hyperinsulinemic hypoglycemia
  • Rare complication of RYGB
  • Pathophysiology: PHH is caused by an exaggerated GLP-1 response in response to meals. After RYGB, food ingestion and rapid gastric emptying trigger a rapid rise in glucose, which stimulates GLP-1 secretion, leading to increased insulin levels. As a result, glucose rapidly declines and hypoglycemia can occur
  • Treatment: Dietary modification, specifically, consuming smaller, more frequent, lower carbohydrate meals.
60
Q

Energy balance hormonal regulation

A
61
Q

Additional comorbidity benefit of liraglutide

A

GLP-1R agonist

Helps treat type II diabetes and prevent development of type II diabetes in pre-diabetic patients

62
Q

Additional comorbidity benefit of topiramate

A

CNS acting

Decreases risk of seizure, prevents nerve pain and headaches

63
Q

Summary of lifestyle-based weight loss therapy

A
64
Q

Specific nutrient risks/benefits

A
65
Q

Specific Diet pros/cons

A
66
Q

BMI Cutoffs for bariatric surgery and weight-loss medications

A
67
Q

Insulin pharmacokinetics

A
68
Q

When adding insulin injection to a diabetes patient’s regimen, how should you manage their other medications?

A

Most medications can and should be kept with the exception of sulfonylureas.

GLP-1 agonists are generally kept, but in more advanced diabetes when a patient needs 3/4 injections of insulin per day, it is not shown to provide any additional benefit, so here it should be removed.

HMS Homeostasis II (35 decks)

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