learning objectives for this file

Adv Pathophysiology Unit 10: Endocrine of 51

File: advpatho_unit10_4pancr_SECTION1.pdf Source: C. DeCristofaro, MD

Learning Objectives for this File: 1. Recognize the difference between the endocrine & the exocrine pancreas 2. Learn about insulin – release, metabolic effects, interactions with other hormones (amylin, incretins) 3. Understand relevance of C-peptide 4. Review the etiology of T1DM 5. Review the etiology of T2DM and related pathophysiology (IRS, dyslipidemia, target organ damage from glycation) 6. Review the categories of DM complications (microangiopathy, macrovascular, other) 7. Appreciate management concerns 8. Review current ADA CPG recommendations for diagnosis & management goals 9. Review special topics in DM



PANCREATIC HORMONES: the other hormones of metabolism REMEMBER the two “parts” of the pancreas” • The Exocrine Pancreas:

o a gastrointestinal organ o produces enzymes, bicarbonate, mucus released directly into gut lumen

• The Endocrine Pancreas: o produces systemically acting hormones released into the bloodstream o with effects on carbohydrate, protein & fat metabolism o synthesizing cells are the “islets” (they appear to be islands floating in the ocean on

gross histology) EXOCRINE PANCREAS

ENDOCRINE PANCREAS



ISLET OF LANGERHANS CELLS: • Alpha cells (25%):

o glucagon (raise glucose levels) • Beta cells (60%):

o insulin (lowers glucose levels) o amylin

co-secreted with insulin in granules lowers glucose levels by reducing glucagon release and regulating stomach

emptying of food into the intestine • Delta cells (10%):

o somatostatin (inhibits both insulin & glucagon release) • PP cell (5%):

o pancreatic polypeptide (effect & function unknown) NOTE: normal endogenous secretion of the pancreatic endocrine hormones goes first to the liver to have immediate effects on hepatic metabolism.



QUICK SUMMARY REGULATORY HORMONES: lower glucose • INSULIN • AMYLIN – anti-glucagon • GUT INCRETINS – insulinotropic, anti-glucagon COUNTER-REGULATORY HORMONES: raise glucose & BP and are hormones of STRESS • glucagon hyperglycemia • Growth Hormone (GH) hyperglycemia • cortisol hyperglycemia, ventilation, immune effects

o also remember, every time cortisol is made, ACTH was made first o when ACTH is made – so are endorphins, MSH, and lipocortin (fatty acids released)

• catecholamines (NE & EP) ventilation, increased CO & BP • thyroxine heat production, visual support, cardiac support, muscle support • many of these also released in pregnancy

o helps explain the glycemia of pregnancy o helps support cardiac, vascular volume, lactation, other adaptive changes in pregnancy



A. INSULIN: metabolism & immunity.

• Insulin is the HORMONE OF ABUNDANCE • a “regulatory” hormone that LOWERS SERUM GLUCOSE LEVELS by moving glucose

into cells • secreted in response to presence of abundant nutrients, and assists in their utilization and

storage. • presence of insulin is lipogenic (creates adiposity)(insulin “packs on the fat”) • First isolated in 1922, a peptide hormone • uses protein kinase second messenger system to phosphorylate cell enzymes • NORMALLY, when insulin is secreted by the pancreas, it FIRST goes to the liver • ***** NOTE: whenever discussing insulin release and regulation of release, also think

“amylin” release, another hormone from the Beta-cell that is co-secreted with insulin in granules *****

• ***** NOTE: whenever discussing insulin release in response to an oral meal, also think of gut incretin hormones (e.g. GLP-1) that are insulinotropic (enhance insulin release, also have effects on stomach emptying, reduce glucagon effects, enhance satiety)

1. Synthesis & Release of Insulin: Synthesis: • as a preprohormone (polypeptide), cleaved (cut) to form proinsulin in the ER of the beta cell • Golgi apparatus cleaves it to form insulin (packaged in secretory granules) • An additional product of this cleavage process is a peptide called C-peptide, that is ONLY

made when endogenous insulin is made Release: • insulin travels in unbound free form in the plasma • half-life of 6 minutes • Completely cleared in 10-15 min by liver & kidney degradation • insulin is released into the portal vein and directly travels to the liver, assisting in prevention of

postprandial hyperglycemia without rebound hypoglycemia. o This is NOT where we give insulin in our diabetic patients o We give it to the peripheral circulation, and mealtime insulin administration often

causes hypoglycemia several hours later !!



Clinical correlate – C-peptide:

• measuring C-peptide tells you how much insulin the pancreas is producing • essentially telling you the health of the pancreas -- can it still produce insulin ??

o Clinical: will the patient benefit from drugs that stimulate insulin secretion?? Should we continue giving these oral hypoglycemic agents? Examples: sulfonylureas

• Also, used forensically to determine if high insulin levels are from endogenous or exogenous (i.e. poisoning) origin.

• Physiology: o C-peptide is produced whenever endogenous insulin is produced, as a byproduct of

the cleavage of the inactive pro-insulin to create active insulin. o A measure of the amount of endogenous insulin being produced by the pancreas. o Measuring C-peptide levels is an indirect way of measuring endogenous insulin

production. o C-Peptide response occurs with endogenous insulin production & not with

exogenously administered insulin. o If someone is using insulin therapeutically, they eventually get insulin antibodies

that interfere with lab testing of actual insulin levels, so insulin levels can’t be measured directly – C-peptide is therefore an indirect measure of their own continuous insulin production.

• Clinical C-peptide testing: o As response to glucagon administration:

1 mg IV glucagon produces pancreatic insulin response o As measure of clinical assessment of current functioning of pancreas:

measuring C-peptide production indicates level of endogenous insulin response.

This may be clinically useful if you are trying to decide to max out your dose of oral hypoglycemic drugs in a diabetic (hoping the pancreas is still working), or just go ahead and start insulin therapy (pancreas has stopped working).

Thus, used by clinicians to assess if any pancreatic activity is still left, and if oral hypoglycemics that stimulate pancreatic insulin secretion will work.

Also, if insulin is STILL being produced, the patient might benefit for the newer “insulin incretin” drugs that HELP insulin work; many T2 DM patients are insulin-TREATED but not necessarily insulin-DEPENDENT

o Forensic uses: determine if insulin levels are due to endogenous (C-peptide found) or exogenous sources (external poisoning with insulin, C-peptide not found).



2. Control of Insulin Secretion: FOOD !! Secretagogues: substances that stimulate insulin secretion. • Glucose:

o insulin secreted if blood glucose levels above 100 mg/dL o Islet cells dump preformed insulin and initial secretion only lasts 10 minutes o Continuous hyperglycemia results in a second insulin secretion 2 - 3 hours later o Once glucose levels fall, insulin release turns off in a few minutes

• Amino acids: o stimulate insulin secretion (some more than others) o cause more insulin to be released when there is hyperglycemia

Gut hormones – “anticipatory release of insulin” – insulinotropic incretin hormones: • gastrin, secretin, CCK, GLP-1 & GIP cause insulin secretion • these are the hormones released on eating a meal and arrival of food in the stomach & small

intestine. • Thus, there is an "anticipatory" release of insulin with an oral meal • Note that these effects do NOT occur with IV glucose administration

The gut hormone incretin effect – only seen in non-diabetics with an ORAL meal: MORE on incretins and also amylin, below…



3. Physiologic effects of insulin: (see pictures below) Insulin effects on cells: • Primary effects:

o Needed to move glucose into most cells (allows cells to be permeable to glucose and activates glucose transporter – GLUT) (see more below)

o Also helps cells become more permeable to amino acids, K+, & phosphate ions o Cells that do NOT need insulin to take up glucose are brain, retina, gonads (&

the fetus) – this is the only source of energy they can use and their uptake is simply dependent on circulating glucose levels

• Secondary effects: o metabolic activity in cell from increased transcription from DNA and translation from

mRNA – so insulin actions can last days o moves potassium into cells o moves sodium into cells but also may activate the Na/K pump and thus throw sodium

out of cells (so sodium effects may be neutral) • Lack of insulin:

o when hypoglycemic (fasting) o if type 1 diabetes mellitus (DM) or end-stage type 2 DM

no release of insulin from the pancreas pancreatic beta-cells cannot perform their function or have been destroyed

Insulin effect on carbohydrate metabolism:

• LOWERS serum glucose, moves glucose into the cells • Muscle cells:

o use glucose preferentially with excercise or after a meal – increased glucose transport into cell by insulin & effect of insulin on cell enzymes

o otherwise use fatty acids. Lack of insulin requires us to use fatty acids for energy because we can’t

move glucose into our cells Develop keto-bodies (keto-acids) acidosis

o stores unused glucose as glycogen • Liver:

o Mealtime glucose stored in liver as glycogen (animal starch) o If excessive glucose stored as fatty acids which in turn become VLDL-C, LDL-C,

TG. o Glycogen stores are used when fasting no hypoglycemia since you breakdown

glycogen to get glucose o During fasting state, liver produces glucose ALSO by gluconeogenesis. o Insulin also inhibits gluconeogenesis.

• Brain, retina, gonads, fetus: o Get enough glucose at all times as long as there is normoglycemia (sufficient serum

glucose levels) o Dependent on glucose in the bloodstream, not on insulin o These tissues are NOT dependent on insulin being present to move glucose

into the cell



Insulin activates intracellular processes that activate GLUT transporter Insulin effects on liver & adipocytes

YouTube Video on the GLUT Transporter: https://www.youtube.com/watch?v=OlHez8gwMgw Insulin effect on fat metabolism on the adipocyte (fat cell): “insulin packs on the fat” • increases utilization of glucose • “fat sparing” – stored fat is NOT used for energy ( obesity) • enhanced fatty acid synthesis (TG sent to fat cells by liver), so more fat sparing ( obesity) • "switches" body back and forth between glucose and fat metabolism

o if a lot of glucose plus insulin use glucose o if not much glucose (or don’t have enough insulin) uses fats

Insulin effect on Protein metabolism & Growth on all cells: • after a meal, insulin inhibits protein catabolism and promotes protein formation/storage

(anabolism), and inhibits gluconeogenesis. • Insulin also is synergistic with GH to promote growth and protein synthesis. • Mechanism:

o promotes transport of all nutrients into cells (carbohydrates, fats, amino acids). o promotes cellular storage of nutrients (insulin turns on ribosomal RNA & DNA

translation to make storage molecules)

https://www.youtube.com/watch?v=OlHez8gwMgw



4. Insulin “Helper” & Insulinotropic Hormones: AMYLIN: • A small polypeptic released in granules, co-secreted with insulin from the pancreatic beta-

cell. • works against glucagon to prevent postprandial hyperglycemia and rebound hypoglycemia

hours later o absent in type-1 diabetes o deficient in type-2 diabetes

• also regulates the emptying of the stomach o there normally isn’t rapid entry of digested foodstuffs into the bloodstream o regulates smooth entry of glucose and prevents postprandial hyperglycemia

• Drug: injectable analog of amylin for diabetics (e.g. Symlin)

GUT INCRETINS – insulinotropics:

• hormones released by the gut to intensify insulin release from the pancreas • It is know that IV glucose administration doesn’t cause as much insulin release as

orally administered glucose • This is the “incretin effect” and is due to gut hormones released after a meal • These include Glucagon-like Peptide (GLP-1) and Gastric-inhibitory Peptide (GIP) • GLP-1 targets:

o alpha-cell of pancreas – prevent glucagon release (like amylin) o beta-cell of pancreas – if glucose is elevated stimulate insulin release (once glucose levels

fall to normal, this “insulinotropic” effect stops, so that you don’t get hypoglycemic) o stomach – slows gastric emptying to prevent rapid rise in glucose with meal o ? brain – reduction in food intake (contribute to satiety and normal eating patterns)

• Overall incretin GLP-1 effects: o inhibits glucagon release (just like elevated blood glucose, amylin, and insulin) o due to the hormonal ratios that change after a meal, cause the liver to switch from glucose

production (gluconeogenesis) to uptake and storage of glucose as glycogen (glyconeogenesis)

o reduces “abnormal feeding” behaviors o helps maintain first-phase insulin release after an oral meal

• They help the non-diabetic person to normalize blood glucose levels after an oral meal • This effect is lost in the diabetic • These gut incretins are degraded (destroyed) by the enzyme dipeptidyl-peptidase 4

(DPP4) • New drug news:

o DDP4 inhibitors (“gliptins”) that keep endogenous GLP-1 around longer, oral drugs (e.g., sitagliptin/Januvia)

o “incretin” mimetics (drugs similar to endogenous GLP-1), injectable (e.g., exenatide/Byetta)

news:o

news:o



B. GLUCAGON: • Secreted from alpha cells of the Islets of Langerhans • causes effects opposite those of insulin; • also a polypeptide hormone. • “counter-regulatory hormone” raises blood glucose • think “stress” & release in hypoglycemic states • Remember:

o Amylin hormone (released with insulin) works against glucagon to prevent postprandial hyperglycemia

o Gut incretins (GLP1, GIP) work against glucagon release and work against glucagon action to prevent postprandial hyperglycemia

THE COUNTER-REGULATORY HORMONES STRESS & ELEVATED GLUCOSE & BP!! • glucagon hyperglycemia • Growth Hormone (GH) hyperglycemia • cortisol hyperglycemia, ventilation, immune effects

o also remember, every time cortisol is made, ACTH was made first o when ACTH is made – so are endorphins, MSH, and lipocortin (fatty acids released)

• catecholamines (NE & EP) ventilation, increased CO & BP • thyroxine heat production, visual support, cardiac support, muscle support • many of these also released in pregnancy

o helps explain the glycemia of pregnancy o helps support cardiac, vascular volume, lactation, other adaptive changes in pregnancy

1. Effects of glucagon on metabolism: Liver:

• glycogenolysis & gluconeogenesis, • Both cause a rapid rise in blood glucose to combat hypoglycemia. • At high levels, inhibits triglyceride storage here and leads to elevated serum TG

Adipocyte (fat cell):

• effect on this cell in starvation • activates adipose cells to breakdown fat into fatty acids for an energy source.

2. Stimulation of glucagon secretion:

• low glucose levels (opposite from insulin). • But high amino acid levels also stimulate glucagon release (same as insulin) (reason is

it uses these amino acids to make glucose in gluconeogenesis) • Exercise causes glucagon release

o prevents hypoglycemia during exercise. 3. Diabetes mellitus:

• NOW thought to also be related to glucagon excess (abnormal regulation of glucagon)

• Not just an insulin and/or amylin deficiency



C. SOMATOSTATIN:

• Made BOTH by the pancreas & the hypothalamus. • Same exact hormone as GHIH (made by hypothalamus to suppress GH secretion from

pituitary). 1. Synthesis & Release:

• Made by the delta cells of the pancreas. • Ingestion of food stimulates this hormone to be released

o glucose, fatty acids, amino acids, & presence of GI hormones of digestion 2. Interaction with other metabolic hormones:

• inhibits both insulin & glucagon release, • decreases GI motility, & • decreases both secretions and absorption in the GI tract.

3. Metabolic role:

• increases time to bring digested foodstuffs into the bloodstream • prevents utilization and exhaustion of new foodstuffs • enhanced use of stored fat & glycogen

4. Drug correlates: • Drug:

o octreotide (Sandostatin) is analog of somatostatin • Label uses:

o Acromegaly from hypersecretory pituitary tumor o Severe diarrhea and flushing from carcinoid tumor o Watery diarrhea from VIP-secreting tumors

• Many off-label uses: o For bleeding esophageal varices o For pain in pulmonary osteroarthropathy from lung cancer (MOA unknown) o In hepatorenal syndrome to improve renal perfusion before liver transplant



MORE ON GLUCOSE METABOLISM: The liver is a “glucose buffer”:

• liver buffers wide fluctuations in blood glucose o stores and releases glucose according to need through control mechanisms of all

the above hormones and their connected feedback systems. o insulin and amylin are directly released to hepatic portal circulation for intimate

regulation of the liver upon receiving foodstuffs from GI tract. o Gut incretins help liver take up glucose and store it as glycogen

• The liver is either: o Performing gluconeogenesis (production of new glucose) or glycogenolysis

(breakdown of glycogen) to provide glucose to the body (in between meals, to prevent hypoglycemia)

o Performing glycogenesis by taking up glucose and storing it as glycogen Glucose-dependent organs: • Must keep constant glucose level – the only nutrient they can use • These organs/tissues are NOT dependent upon insulin for entry into the cells • Include:

o brain o retina (really brain tissue) o germinal epithelium of gonads o fetus

• Clinical correlate: o HYPOGLYCEMIA due to increased INSULIN will preferentially bring glucose into

the peripheral cells and take it away from the brain o Depending on genetics, SOME people’s brain may be able to metabolize other

carbohydrates, so they may not be completely dependent on glucose and not as much at risk of hypoglycemia (but no way to predict this in advance)



Osmotic activity of glucose – WHY glucosuria & polyuria if hyperglycemic?

• Glucose has osmotic activity • If glucose “spills” into urine (glucosuria), it will drag water along with it and thus cause

polyuria (increased urinary volume) • This loss of fluid will cause dehydration and polydipsia (increased thirst) • CLINICAL:

o Normally, when clinicians talk about when glucosuria will appear, they want to know at what blood level of glucose "spillage" will start to happen. Years ago, before the easy ability to measure blood glucose, we used the amount of glucose in the urine as an indirect measure of blood glucose and treated accordingly.

o Transport maximum (Tmax): glucose transporter is saturated at tubular filtrate glucose concentrations of 300 mg% (300 mg/dL also called 300 mg/ 100 mL).

o Renal threshold: when the level of blood glucose will cause a tubular glucose level high enough to saturate the transporter; this begins at approximately 180mg/dL (180 mg%). So from a clinical standpoint, at what blood glucose do we start to see glucosuria? At 180 mg% and above.



DIABETES MELLITUS: Genetic disease a “multi-hormone” problem: • LACK OF INSULIN & LACK of AMYLIN & LACK OF INCRETIN EFFECT • TOO MUCH GLUCAGON • Lack of insulin/amylin is eventually outcome of both types of diabetes • Type 1 (T1DM): (also called T1D)

o autoimmune destruction of beta-cells and lack of insulin (& amylin) production • Type 2 (T2DM): (also called T2D)

o insulin resistance (lack of sensitivity) hyperinsulinemia (to overcome the resistance) eventual burnout of beta-cells and no insulin (or amylin)

What do the words mean?

• The word "diabetes" is borrowed from the Greek word meaning "a siphon" – the 2nd-century CE Greek physician, Aretus the Cappadocian explained that patients with it had polyuria and "passed water like a siphon."

• The word “mellitus” is derived from the Latin word for “honey” and refers to the sweet taste of the urine. Usually, if only the word “diabetes” is used, it refers to diabetes mellitus and not diabetes insipidus (insipid means “flavorless”).

Prevalence of DM is increasing:

• Prevalence overall is 12-14% of US adults • Higher prevalence among non-Hispanic black, non-Hispanic Asian, and Hispanic • Prevalence is increasing in all subgroups

Prediabetes (“at risk” for DM) and Prevention of T2DM: • people who are in the process of developing T2DM take many years to finally have the

diagnosis • as they progress towards T2DM they are prediabetic (also called “at risk” for DM) with

elevations of blood glucose that are not as great as actual T2DM • prevention of T2DM is part of the management of prediabetes Gestational diabetes (GDM): • women who are pregnant may develop diabetes • only certain drugs can be used – usually insulin is the mainstay • goals of therapy are specifically defined for this population – “tight” glucose control to

minimize maternal and fetal complications



Potential Complications of DM: • practice guidelines related to complications of diabetes • these include foot infections, nephropathy, neuropathy, cardiovascular disease Example – current diabetic retinopathy screening & treatment recommendation:



Metabolic consequences of insulin deficiency: • protein starvation & poor wound healing (collagen is a protein) • ketogenic effect from mobilization of fats (free fatty acids & keto-bodies)

o decreased utilization of glucose & hyperglycemia o secondary osmotic diuresis plus increased blood osmolality & cell shrinkage,

dehydration, polydipsia & polyuria from osmotic diuresis • Cells are actually starving despite the serum hyperglycemia weight loss & polyphagia. • microvascular effects microangiopathy (small blood vessel damage):

o causes secondary organ complications of neuropathy, retinopathy, nephropathy (basement membrane destruction at the glomerulus with proteinuria)

• cardiomyopathy from insulin-like growth factors. • macrovascular effects:

o effects on medium/large arteries o atherosclerosis from abnormal fat metabolism (accelerated by Angiotensin-II)

Abnormal proteins: • glycation (glycosylation) chemical reaction

o addition of glucose to proteins (non-ezymatic process) alters proteins and makes them abnormal

o this creates advanced glycation end products (AGEs) organ damage o also contributes to microangiopathy (destruction & pathology of micro-capillaries that

feed tissues) • Examples:

o retinopathy o Nephropathy: abnormal sialoproteins of basement membrane of glomerulus in

Kimmelstiel-Wilson kidney with proteinuria (proteinuria seen) o Cataracts: lens protein no longer clear

Immune system dysfunction:

• It AIN’T ALL METABOLISM that is wrong !! • PMN dysfunction with • reduced WBC chemotaxis & phagocytosis • at risk of infection



Overview of categories of DM: Type-1 (formerly, insulin-dependent DM, or IDDM) – T1DM (T1D): • no longer called IDDM (insulin-dependent DM) & is no longer called type-I (the Roman

numeral caused chart errors) • 8% of all diabetics • The hallmark is the development of ketoacidosis if left untreated (due to absence of insulin) &

the need for exogenous insulin to prevent ketoacidosis • Etiology:

o autoimmune etiology with genetic predisposition to develop antibodies against pancreatic beta-cell antigens

o usual presentation at younger age (pediatric presentation, usually after a stress such as infection)

• Is there a cofactor that is an environmental toxin trigger? o a toxin ? infection ? dietary ? (? beta-casein cross-reactivity in cow's milk ?) o now it is thought that insulin itself is the trigger to develop autoantibodies and possibly

early exposure to oral insulin may prevent T1DM in at-risk children; see: Bonifacio, E., et al. (2015) Effects of high-dose oral insulin on immune responses in children at high risk for type 1 diabetes, JAMA, 313(15), 1541-1549. doi 10.1001/jama.2015.2928

• T1DM usually presents with extreme hyperglycemia, ketoacidosis, pediatric “Type-1.5” Diabetes? Type 1b Diabetes? LADA (latent autoimmune diabetes in adults): • Also sometimes called delayed onset DM • Subtype of T1DM, there is a positive FH for T1DM • Thin diabetics diagnosed ages 20-40 yo • Positive antibodies to islet-cell antigens (ICAs) • Management is just like T1DM (Rare) Monogenic Diabetes of Youth (Maturity Onset Diabetes of the Young, MODY):

• Due to a SINGLE mutation in a SINGLE gene – as opposed to most DM which is polygenic • May present as neonate or in youth; genetic testing determines treatment • See NIDDK: https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-

diabetes/monogenic-neonatal-mellitus-mody?dkrd=hispw0033 and University of Chicago (nice overview) https://monogenicdiabetes.uchicago.edu/what-is-monogenic-diabetes/

https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/monogenic-neonatal-mellitus-mody?dkrd=hispw0033

https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/monogenic-neonatal-mellitus-mody?dkrd=hispw0033

https://monogenicdiabetes.uchicago.edu/what-is-monogenic-diabetes/

https://monogenicdiabetes.uchicago.edu/what-is-monogenic-diabetes/



Gestational DM (GDM): • placed in classes based on OGTT/FPG/2-hr postprandial (PP) glucose values • Etiology:

o hormones of pregnancy (counter-regulatory hormones ) o may result in "unmasking" of previously unsuspected DM o Usually returns to baseline after delivery of fetus.

• Diagnostic classes: class drives therapeutic decisions o "A" class of onset during gestation; B - H classes that occur at younger ages, with

longer duration, or with complications (e.g. nephropathy). o Usually need tight control, so cutoff points are quite low. o The only class that allows for diet therapy is the "A1" class (FPG<105 mg/dL & 2-hr

postprandial glucose<120 mg/dL); all other classes above these values require insulin therapy (i.e. FPG > 105 mg/dL & 2-h PP glucose > 120 mg/dL).

• Gestational DM guidelines: • ADA 2020: https://care.diabetesjournals.org/content/43/Supplement_1/S183



Type 2 DM (formerly, non-insulin dependent diabetes, or NIDDM, or type-II) – T2DM (T2D): • no longer called NIDDM (non-insulin-dependent DM) and is no longer called type-II (use the

Arabic numeral, not Roman numeral) • 92-95% of all diabetics (153 million Americans), with 20% requiring insulin. • The Iceland DeCode project found a single genetic change predisposes 40% of Northern

Europeans to T2DM; gene also common in African-Americans; called TCF7L2 on chromosome 10q (it produces a transcription factor, that controls another gene)

• Usual onset is adulthood (& now we are seeing onset in adolescents). • Used to be called a "milder" disease only because there is no ketoacidosis, BUT ALL OTHER

complications still ensue at the same rate; and hyperglycemic coma can develop – don’t use this term “milder”

• Continuum: o Insulin resistance hyperglycemia o Hyperglycemia more insulin (hyperinsulinemia) insulin “packs on the fat” o MORE hyperglycemia from worsened insulin resistance o So that PREDIABETES finally becomes overt DIABETES

• Etiology: genetic syndrome (more below on mechanism of disease) o insulin resistance syndrome (IRS) (tissue insensitivity to insulin, glucose

remains in blood) o abnormal insulin & amylin release (too late, too much, too long) o abnormal incretin response

• Related pathology: o Prothrombotic syndrome with elevated C-reactive protein (CRP) and fibrinogen o Accelerated atherosclerosis o Abnormal lipid metabolism o Eventual loss of pancreatic function, less to NO insulin production at the end.

worsened by improper diet (glycemic or low fiber) worsened by obesity

o Obesity may be determined by genetics – adipocyte hormones: leptin (too little is linked to abnormal satiety & obesity) resistin (linked to insulin resistance) adiponectin (too little atherosclerosis & insulin resistance)

Note that ALL diabetics are also in a pro-coagulative state and are pro-thrombotic, thus at risk thrombotic events.



Mechanisms of T2DM – COMBINATION OF: • Insulin resistance in peripheral cells (see below) • Abnormal insulin release at mealtimes • Abnormal amylin release • Abnormal incretin response • Final effect is hyperinsulinemia and hyperglycemia

Etiology of T2DM – the “lipocentric” pathway: • Caloric surplus hyperinsulinemia increased genome expression of lipogenic transcription

factor SREBP-1c • Increased lipogenesis (making fat cells and storing fat) increased adiposity and ectopic lipid

deposition (abdominal obesity) • Insulin resistance beta-cell lipotoxicity (damages pancreatic beta cells) hyperglycemia Abnormal carbohydrate metabolism: • Insulin Resistance Syndrome (IRS):

o insulin resistance syndrome (IRS) – tissue insensitivity to insulin so glucose is not taken up by cells

o progressive obesity and hyperinsulinemia • Abnormal insulin release:

o Delay or loss of “first phase” insulin release, postprandial hyperglycemia (glucose spike) occurs, contributing to prolonged hyperglycemia and raising the A1C

o When insulin is FINALLY released, it has a prolonged release that contributes to INCREASED exposure of the body to insulin levels and thus contributes to the “fat packing” effects of hyperinsulinemia and the progressive weight gain seen in this condition, which in turn worsens IRS

o Eventual loss of pancreatic function, less insulin production, less amylin production, loss of incretin effect

o Worsened by obesity, high glycemic or low fiber diet o Obesity may be determined by genetics

Adipocytes make two hormones, leptin (linked to abnormal satiety) and resistin (linked to insulin resistance).

SEE GRAPHICS BELOW…



Too much insulin, too late, for too long

Results in basal and post-prandial (PP) hyperglycemia compared to nondiabetic



Insulin Resistance Syndrome (IRS) is the hallmark of T2DM: • in addition to abnormal insulin/amylin release and abnormal incretin response, IRS is related

to most (if not all) of the related pathologies in T2DM o Thrombotic risk o Accelerated atherosclerosis o Obesity o Hypertension worsened

• Dyslipidemia worsened Clinical characteristics of Insulin Resistance Syndrome (IRS): • Central obesity (women waist > 35”, men > 40”) • Elevated BP 160/90+ • Elevated TG (150 mg/dL+) • Low HDL-C (women < 50 mg/dL, men < 40 mg/dL) • Elevated LDL-C (bad cholesterol) > 100 mg/dL • Elevated glucose (FPG >= 126 mg/dL) • Microalbuminuria 20 mcg/min+ or albumin:creatinine ratio • Extremely similar to metabolic syndrome (MetS)(extreme high risk of cardiovascular

disease)



OVERALL ALTERATIONS IN T2DM LEADING TO HYPERGLYCEMIA: A continuum from normoglyemia through prediabetes (at risk for diabetes) to overt T2DM From: ismail-Beigi F. Glycemic management of type 2 diabetes mellitus. N Engl J Med 5 April 2012;366(14):1319-27. (with permission) Prediabetes (“at risk” for diabetes):

• Formerly called IMPAIRED FASTING GLUCOSE (IFG), and/or IMPAIRED GLUCOSE TOLERANCE (IGT)

• Both these terms are now included in “prediabetes” and the phrase “at risk” for diabetes • You are prediabetic (at risk for diabetes):

o if your FPG is 100-125 mg/dL o OR if your A1C is 5.7-6.4% o OR if your 75g OGTT 2-hr glucose 140-199 mg/dL

See ADA website on prediabetes: https://www.diabetes.org/diabetes-risk/prediabetes

https://www.diabetes.org/diabetes-risk/prediabetes



Prevalence of T2 DM is increasing in the USA: From: Menke, A., et al. (2015) Prevalence of and Trends in Diabetes Among Adults in the United States, 1988-2012. JAMA, 314(10), 1021-1029. doi:10.1001/jama.2015.10029



LINKS TO SPECIFIC CLINICAL TOPICS IN DIABETES: Clinical practice guidelines (CPGs) from the ADA are updated every JANUARY: • American Diabetes Association (ADA): https://www.diabetes.org/ • Updated annually every January – for 20209 Standards of Care for DM:

https://professional.diabetes.org/content-page/practice-guidelines-resources Pediatric guidelines for T2DM in CHILDREN: From the ADA 2020: https://care.diabetesjournals.org/content/43/Supplement_1 From the American Academy of Pediatrics (AAP):

1) Copeland KD, et al. Management of Newly Diagnosed Type 2 Diabetes Mellitus (T2DM) in children and Adolescents. February 7 2013, Pediatrics; 131:364. Available at: https://pediatrics.aappublications.org/content/131/2/364

2) Springer SC, et al. Management of Type 2 Diabetes Mellitus in Children and Adolescents. January 28 2013, Pediatrics; 131(2): e648-e664.

(doi: 10.1542/peds.2012-3496) Available at: https://pediatrics.aappublications.org/content/131/2/e648

Gestational DM (Diabetes in Pregnancy) guidelines:

• ADA 2020: https://care.diabetesjournals.org/content/43/Supplement_1/S183 Other sites and CPGs related to DM: 1) NDEI National Diabetes Education Initiative: http://www.ndei.org 2) American Association of Clinical Endocrinologists (AACE) guide the ADA:

https://www.aace.com/ 3) Prediabetes & Prevention of DM – nice website for patient education: https://www.diabetes.org/diabetes-risk/tools-know-your-risk 4) National Institute of Diabetes and Digestive & Kidney Diseases (NIDDK):

https://www.niddk.nih.gov/ 5) LEAP (Lower Extremity Amputation Prevention): https://www.hrsa.gov/hansens-disease/leap

AND order your OWN free monofilament TEST KIT: https://www.hrsa.gov/hansens-disease/leap/order-test-kits

Used in physical exam testing for diabetic neuropathy of the lower extremity (foot/lower leg)

https://professional.diabetes.org/content-page/practice-guidelines-resources

https://pediatrics.aappublications.org/content/131/2/364

http://www.ndei.org/

https://www.aace.com/

https://www.niddk.nih.gov/

https://www.diabetes.org/

https://care.diabetesjournals.org/content/43/Supplement_1

https://pediatrics.aappublications.org/content/131/2/e648

https://care.diabetesjournals.org/content/43/Supplement_1/S183

https://www.diabetes.org/diabetes-risk/tools-know-your-risk

https://www.hrsa.gov/hansens-disease/leap

https://www.hrsa.gov/hansens-disease/leap/order-test-kits




The MAIN CATEGORIES of DM:

• Type 1 DM (T1DM) – autoimmune beta-cell destruction • Type 2 DM (T2DM) – progressive beta-cell secretory dysfunction & peripheral insulin

resistance • Gestational DM (GDM) • There are also other, rarer forms – more later



2020 CRITERIA FOR DIAGNOSIS OF PREDIABETES (“INCREASED RISK FOR DM”): KNOW THESE NUMBERS

• Formerly called IMPAIRED FASTING GLUCOSE (IFG), and/or IMPAIRED GLUCOSE TOLERANCE (IGT)

• Both these terms are now included in “prediabetes” and the phrase “at risk” for diabetes • You are prediabetic (at risk):

o if your FPG is 100-125 mg/dL o OR if your A1C is 5.7-6.4% o OR if your 75g OGTT 2-hr glucose 140-199 mg/dL

See: https://www.diabetes.org/diabetes-risk/prediabetes FOR CONSUMERS:

• The Diabetes Risk Test • See: https://www.diabetes.org/risk-test (works best in Chrome browser)

https://www.diabetes.org/diabetes-risk/prediabetes

https://www.diabetes.org/risk-test



2020 SUMMARY FOR DM DIAGNOSIS (nonpregnant adults): KNOW THESE NUMBERS • You are NON-DIABETIC if your fasting glucose is < 100 mg/dL (100 mg %) and your

A1C is <5.7% • You are PREDIABETIC (also called “at risk” or “increased risk” for diabetes) if your

fasting glucose is 100 – 125 mg/dL (older terms are “impaired fasting glucose”(IFG) and “impaired glucose tolerance” (IGT) OR your A1C is 5.7-6.4%

• You are DIABETIC if your fasting glucose is 126+ mg/dL (126 and over) OR your A1C is 6.5% or greater OR any random blood glucose is over 200 mg/dL and you have symptoms of diabetes (any one of these tests can be used for T2DM; for acute onset symptomatic T1DM, use blood glucose and not A1C)



Glucose Testing and Interpretation

Test Result Diagnosis

Fasting plasma glucose, mg/dL ≤99 Normal

100-125 Impaired fasting glucose

≥126 Diabetes, confirmed by repeating the test on a different day

Glucose, mg/dL (oral glucose tolerance test, 2 hours after ingestion of 75-g glucose load)

≤139 Normal

140-199 Impaired glucose tolerance

≥200 Diabetes, confirmed by repeating the test on a different day

Hemoglobin A1C, % (as a screening test) ≤5.4 Normal

5.5-6.4 High risk/prediabetes; requires screening by glucose criteria

≥6.5 Diabetes, confirmed by repeating the test on a different day



SCREENING FOR DM & PREDIABETES IN ASYMPTOMATIC ADULTS 2019: If no risk factors, universal screening at age 45 yo & repeated Q 3years Note increased criteria for screening in some subpopulations

From the US Public Service Task Force: https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/screening-for-abnormal-blood-glucose-and-type-2-diabetes

https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/screening-for-abnormal-blood-glucose-and-type-2-diabetes

https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/screening-for-abnormal-blood-glucose-and-type-2-diabetes



The Diabetes Risk Test See: https://www.diabetes.org/risk-test (works best in Chrome browser)

https://www.diabetes.org/risk-test



SCREENING FOR T2DM IN ASYMPTOMATIC CHILDREN 2020:



WAYS TO CLINICALLY CATEGORIZE DM COMPLICATIONS: Microvascular: Tight glucose control can prevent these types of complications (UKPDS Study – United Kingdom Prospective Diabetes Study, ended 1997). • retinopathy – reduced by ¼ (& eye disease overall by 1/3) • nephropathy (basement membrane disease, Kimmelstiel-Wilson) – reduce 1/3 • neuropathy (peripheral, autonomic, & mono-neuropathies such as optic nerve) • skin ulcers • Etiology of microvascular damage:

o glycation (glycosylation) which is adding glucose to body proteins in target tissues (e.g. glycosylation of clear proteins in the lens, making them cloudy & causing cataracts). This process leads to advanced glycation endproducts (AGEs) that are thought to be etiologic

o presence of transforming growth factor-beta linked to diabetic nephropathy and accelerated ASHD (macrovascular)

Macrovascular: what is killing the diabetic early is atherosclerosis • In T1DM as well as T2DM, tight glycemic control CAN reduce CV events • Also, remember the focus on CV risk factors (HTN, lipids) • presence of transforming growth factor-beta linked to diabetic nephropathy and accelerated

ASHD (macrovascular) o coronary artery disease (angina, MI) & cerebrovascular disease (stroke, CVA) –

reduced by 1/3 if achieve glucose, BP & Lipid goals o peripheral arterial disease (PVD)

Other: • EYE: cataracts, corneal erosion, glaucoma, retinal holes/detachments • impaired immune function (impaired chemotaxis & phagocytosis of WBC) • arthropathy • may be an independent risk factor for development of liver cancer in those over age 65 yo • Musculoskeletal:

• up to 1/3 of DM patients may have stiff-joint syndrome from collagen damage due to glycation

• appear to have tight, waxy skin and joint stiffness • prayer-sign exam (unable to put together palms/fingers) • Xray is Lateral Neck Xrays in extension • will be difficult to intubate

Clinical management of DM – aiming to PREVENT complications: • Lab blood glucose levels and patient self-management of blood glucose (SMBG) • Averages the glucose level over 3 months – use hemoglobin A1C • Usually called the A1C (older names glycosylated hemoglobin & glycohemoglobin)

o Measures long-term glycemic control – this is the glucose attached to the Hb molecule via glycosylation reaction

o A1C > 7% associated with risk of TOD (cataract, retinopathy, nephropathy)



MORE ON DIABETIC SPECIFIC COMPLICATIONS: most of this info from UKPDS & DCCT studies Clinical Presentation of DM: • Initial Lab:

o hyperglycemia o glucosuria with urine spillage over renal threshold of serum glucose of 180 mg/dL o polyuria that develops from osmotic diuresis from excess glucosuria o cells starving – weight loss, polyphagia

• Potential for Diabetic Keto-Acidosis (DKA) in T1DM: no insulin ketoacidosis o Acidosis (keto bodies) from hepatic oxidation of free fatty acids released from

adipocytes for energy (most are beta-hydroxy-butyrate and are out of normal balance with aceto-acetate and acetone)

o Acidosis from reduced bicarbonate o Kussmaul breathing with possible coma o glucose levels may not be that high, but always measure ketones to check for DKA and

get an ABG o may present as an acute abdomen

• Potential for Non-ketotic hyperosmolar coma (NKHC) in T2DM: o Also called Hyperglycemic Hyperosmolar Syndrome (HHS) o very high glucose levels o less likely to be ketotic as compared with the T1DM, but ketones should be checked if

blood glucose is above 240-250 mg/dL o associated with CNS changes

• Clinical issues in BOTH types of DM: o Fatigue (asthenia) o Polydipsia (osmotic diuresis –> dehydration) o Polyuria (osmotic diuresis) o Polyphagia (cells are starving despite high serum glucose) o Weight loss o Abnormal proteins (cataracts) -- glycosylation (glycation) o Microvascular (glycosylation/glycation)

Microangiopathic retinopathy Neuropathy Nephropathy (KW disease) with proteinuria (albuminuria)

o Increased susceptibility to infection (immune dysfunction) o Poor wound healing. o Macrovascular -- atherosclerosis (MI, CVA, TIA)



Production of abnormal proteins: • glycation (glycosylation) chemical reaction

o addition of glucose to proteins (non-ezymatic process) alters proteins and makes them abnormal

o this creates advanced glycation end products (AGEs) organ damage o also contributes to microangiopathy (destruction & pathology of micro-capillaries that

feed tissues) • Examples:

o retinopathy o Nephropathy:

• abnormal sialoproteins of the basement membrane of the glomeruli in Kimmelstiel-Wilson kidney (with resultant proteinuria)

o Cataracts: lens protein no longer clear



Target Organ Damage (TOD): due to the GLYCATION REACTION • tight glycemic control can slow TOD development & even cause TOD regression (e.g.

nephropathy) (UKPDS – United Kingdom Prospective Diabetes study) • Etiology (except for the immune function effects) due to the glycation (glycosylation)

reaction o Excess glucose attaches to proteins o These “glycated” (glycosylated) proteins are no longer normal o They are called “glycation end products” o Examples:

lens proteins (normally clear) becoming opaque (cataract) abnormal sialoproteins in glomerular basement membrane (diabetic K-W

nephropathy) • Each "spike" of uncontrolled hyperglycemia therefore directly leads to TOD

complications – it is our job to prevent this with proper management

“Spikes” of glucose elevations: • both fasting & post-prandial hyperglycemia • Each “spike” of uncontrolled hyperglycemia directly leads to complications • Retinopathy ocurs at glucose values > 110 mg/dL • Post-prandial glucose should be kept at < 140mg/dL (2h post meal) • Post-prandial hyperglycemia only recently recognized as major contributor to A1C levels

(formerly thought mostly due to fasting blood glucose elevations)



Typical natural history of T2DM – if aggressive treatment is not instituted early:

Diabetic retinopathy: Development associated with A1C>7%

Relationship of A1C with development of Diabetic retinopathy: Notice the sharp rise at A1C of 7% and above



Diabetic retinopathy:

Retinopathy Exudates

The ACCORD study (2010): • Many of our current recommendations for care come from this study • Intensive glycemic control (A1C ,6.5%) and intensive combination therapy for dyslipidemia

(fenofibrate plus statin) reduced rate of progression of retinopathy • Intensive control of BP did not show this benefit

From: Antonetti DA, et al. Diabetic retinopathy. N Engl J Med 29March 2012;366(13):1227-39. (with permission)



More resources on DM retinopathy: • What is Retinopathy from the American Academy of Ophthalmology:

https://www.aao.org/eye-health/diseases/what-is-diabetic-retinopathy • Retinopathy guidelines from AAO: https://www.aao.org/preferred-practice-pattern/diabetic-

retinopathy-ppp-updated-2017 • ADA position statement on retinopathy: https://care.diabetesjournals.org/content/40/3/412

Stages of DM retinopathy:

https://www.aao.org/eye-health/diseases/what-is-diabetic-retinopathy

https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp-updated-2017

https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp-updated-2017

https://care.diabetesjournals.org/content/40/3/412



Diabetic retinopathy screening & treatment recommendations 2020:

Intravitreal injections of laser photocoagulation of diabetic proliferative retinopathy?

• Intravitreal injections of drugs that block vascular endothelia growth factor (VEGF) such as ranibizumab (Lucentis) work as well as photocoagulation (laser therapy

• See “what is Lucentis”: https://www.lucentis.com/wet-amd/patient-information/why-lucentis.html

https://www.lucentis.com/wet-amd/patient-information/why-lucentis.html

https://www.lucentis.com/wet-amd/patient-information/why-lucentis.html



MORE ON OTHER COMPLICATIONS: Macrovascular: what is killing the diabetic early is atherosclerosis • In T1DM as well as T2DM, glycemic control CAN reduce CV events • Also, remember the focus on CV risk factors (HTN, lipids) • presence of transforming growth factor-beta linked to diabetic nephropathy and accelerated

ASHD (macrovascular) o coronary artery disease (angina, MI) & cerebrovascular disease (stroke, CVA) –

reduced by 1/3 if achieve glucose, BP & Lipid goals o peripheral arterial disease (PVD)

• remember the possibility of silent MI in DM (can be diagnosed via cardiac MRI) Hypertension and T2DM: • Insulin resistance triggers other body systems that lead to HTN – these include:

o Renal sodium retention and salt/volume loading o Sympathetic NS activation o Growth promotion of vascular smooth muscle o Overall vasoconstricton

Hypertension screening 2020:



Hypertension treatment goals 2020:



Immune system dysfunction:

• It AIN’T ALL METABOLISM that is wrong !! • PMN dysfunction with reduced WBC chemotaxis & phagocytosis • at risk of infection

Diabetic gastroparesis: • sense of early fullness while eating and “bloating” sensation • delayed emptying may cause rise in post-prandial blood glucose • prokinetic agents would relieve this • FDA label approved:

o metoclopramide (Metozolv) o remember that LONG-TERM use of this drug can cause extra-pyramidal syndrome (EPS),

such as tardive dyskinesia & Parkinsonism o remember risk of seizure, cardiac problems



Autonomic Dysfunction (a type of Neuropathy): • after having DM for years may develop autonomic dysfunction, possibly due to neuropathy

of the nerves of the ANS o may be due to nerve damage from chronically elevated or repeated “spikes” of

hyperglycemia o may be due to repeated episodes of hypoglycemia – hypoglycemia associated

autonomic failure (HAAF) • results in abnormal sensory

o the patient may be unaware of hypoglycemia o the patient may be unable to feel visceral pain (they may have a silent MI)

• results in abnormal efferent (motor) o they may develop diabetic gastroparesis (poor gastric emptying) o they may have abnormal cardiac reflexes (resting pulse > 90 bpm)

• may present as a silent MI (silent heart attack)

From (with permission): Cryer PE. Mechanisms of Hypoglycemic-Associated Autonomic Failure in Diabetes. N Engl J Med 25 July 2013;369(4):362-72.



Other: • EYE: cataracts, corneal erosion, glaucoma, retinal holes/detachments, retinopathy • impaired immune function (impaired chemotaxis & phagocytosis of WBC) • arthropathy • may be an independent risk factor for development of liver cancer in those over age 65 yo • Musculoskeletal:

o up to 1/3 of DM patients may have stiff-joint syndrome from collagen damage due to glycation

o appear to have tight, waxy skin and joint stiffness o prayer-sign exam (unable to put together palms/fingers) o Xray is Lateral Neck Xrays in extension o will be difficult to intubate during resuscitation or surgery/anesthesia

Mortality increase due to DM: (From: The Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 3 March 2011;364(9):829-41.)



Diabetic distal polyneuropathy (peripheral neuropathy) (DPN): • microvascular complication (nerves deprived of blood flow & oxygen) • metabolic effects on nerve cells (sorbitol in nerve cells, or a decrease in myoinositol, or

peripheral nerve glycosylation, or hypoxia) • DPN includes sensory polyneuropathies

o usually distal & symmetrical o smaller fibers causing the pain & paresthesia symptoms o larger fibers the loss of vibratory & position sense o including loss of stretch reflexes (diminished ankle reflexes).

• Can use a microfilament for quantitative sensory testing. • Vascular risk factors accelerate development of DPN • DPN may also signal risk of developing Charcot joint (neurovascular skeletal complication) • Treatment:

o Tight glycemic control (DCCT showed 69% reduction in DPN over 5 years) o Antidepressants (TCAs, SSRIs, SNRIs) – duloxetine (Cymbalta) label-approved (may

cause changes in blood glucose with impaired control) o Anti-epileptics (gabapentin, carbamazepine) and label-approved pregabalin (Lyrica) o Topical capsaicin 0.075% (Zostrix)

CPG 2011 from American Academy of Neurology: https://www.aan.com/Guidelines/home/GetGuidelineContent/480

Above chart from: Vinik, A.I. (2016) Diabetic Sensory and Motor Neuropathy. N Engl J Med, 374(15), 1455-1464. DOI: 10.1056/NEJMcp1503948 Retrieved from https://www.nejm.org/doi/full/10.1056/NEJMcp1503948

https://www.aan.com/Guidelines/home/GetGuidelineContent/480

https://www.nejm.org/doi/full/10.1056/NEJMcp1503948



FOOT EXAM FOR NEUROPATHY SCREENING IN DIABETES MELLITUS: Diabetic foot ulcer: • educate regarding prevention of foot problems with proper foot care • note the relationship of development of diabetic foot ulcer with sensory, autonomic and motor

neuropathies From: Armstrong, D.G. & Boulton, A.J.M. (2017) Diabetic foot ulcers and their recurrence. N Engl J Med, 376(24), 2367-75. Retrieved from https://www.nejm.org/doi/pdf/10.1056/NEJMra1615439

https://www.nejm.org/doi/pdf/10.1056/NEJMra1615439



Loss of sensation: • Risk for foot ulcers and their sequelae (including amputations) • Loss of “pain warning system” due to neuropathy, most commonly from DM • Low risk: Intact sensation, no prior foot ulcer, no amputation, pedal pulses present, no

severe deformity (all must be present) • High risk: loss of sensation, poor/absent pedal pulses, prior amputation, severe foot

deformity, h/o foot ulcer (any of these) Recommendations:

• Daily self-assessment by patient (patient handouts available) if any loss of sensation; peform monofilament testing every month

• Inspect feet visually every visit and perform additional foot testing based on RISK assessment

• Referral to foot specialist if abnormal findings – will involve more extensive testing, prescription footwear.

Basics of neuropathy SCREENING for diabetic peripheral neuropathy (DPN): • Looking at the foot as a neurologic exam for distal symmetric polyneuropathy • Assessment:

o Assess for foot deformity, tenderness, sores, poor wound healing, toenails o Perform vascular exam (pt, dp pulses); check skin (accessory structures of skin?) o Ask about claudication, burning or stinging sensations o Check for edema, ulcers, skin breakdown, dry/cracked skin o Use 5.07 monofilament sensory test – touch with sufficient force to bend

monofilament, hold in place for 1-2 seconds; use random sequence; write in on picture

o If area is covered by callus, test nearby area o Ask if patient can feel sensation or if any burning sensation with monofilament

• Temperature probe: measure skin temperature to signal inflammation tell patient to reduce activity to prevent DM foot ulcers (TempTouch Infrared probe)

• Neuropathy screening methods: vibration perception, light touch (10-gram monofilament), deep tendon reflexes (DTRs)

Right Left Monofilament testing for neuropathy at these sites

See LEAP program website to order free monofilament kit and also patient resources.

ADA 2017 peripheral neuropathy guidelines:



ADA 2020 diabetic neuropathy screening & treatment: Charcot Joint (Charcot foot) • Neuropathy testing with monofilament helps identify patients at risk of this complication

o Looking for LOSS OF PROTECTIVE SENSATION (LOPS) • Charcot joint is a complication of neuropathy

o neurotraumatic theory: bone trauma due to loss of normal pain & proprioception, resulting in unintentional foot trauma

o neurovascular theory: autonomic dysregulation (hyperemia, osteopenia) • Presents with swelling (progresses to foot deformity), temperature elevation, redness, but little

or no pain o there is a sudden softening of the bones of the feet – initial Xrays may be normal o treatments includes immobilization, reduction in patient activity & weight bearing, as

well as other modalities (& and surgery) o requires referral to foot specialist for braces, casting

Late stage “Rocker-bottom foot” of Charcot

Order your free monofilament TEST KIT: https://www.hrsa.gov/hansens-disease/leap/order-test-kits





Charting findings from examination or screening: • Ulcer classification: grade, depth, site, clinical description of wound • Ulcer etiology: mechanical, thermal, chemical trauma • Vascular abnormalities:

o pulses, ankle-brachial index (ABI), toe pressures, TcPO2 • Infection: chart exam findings and results of diagnostics

o cultures, radiographs, probe (for bone), scans, MRI • Limb deformity complications:

o callus, hammertoes, bunion, Charcot joint, amputation • Temperature probe:

o measure skin temperature to signal inflammation • Neuropathy screening:

o vibration perception, light touch (10-gram monofilament), deep tendon reflexes (DTRs) Treatment of diabetic neuropathy and complications: • Debridement:

o all necrotic tissue o surgical and/or medical

• Pressure reduction: o “off-loading” to enhance healing (crutches, padding, contact cast, walking brace, etc.)

• Infection: o I&D, antibiotics, resection/amputation

• Vascular: o Bypass surgery

• Medical: o Achieve normoglycemia, normotensive BP o Provide nutritional support, renal support & protection, cardiovascular prophylaxis as

indicated • Reduce recurrence of pressure complications:

o followup with podiatrist o education o prescribed footwear o surgery to reduce pressure points

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