DIABETES

INSULIN
- Hepatic Glucose Production = primary factor determining fasting glucose levels
o Regulated by
Fasting plasma insulin
Hepatic sensitivity to insulin
Fasting substrate availability (amt of sugar/fat already present)
o Basal insulin is just enough to suppress hepatic glucose production to the rate of
glucose uptake
Insulin independent tissues (utilize glucose)
Brain & kidney
GLUT-2 transporter
Insulin dependent tissues (utilize FFAs from TGs)
GLUT-4 transporter [req. an insulin signal!]
Aquapores
- Glucose/Insulin Action
o 2 phases (180 min)
1. Rapid release of insulin (~10 min) this is when insulin is most effective!
Hepatic glucose production is suppressed
2. Sustained release over time
o Works at liver first (40%) then goes to rest of insulin sensitive tissues
- Human insulin
o Self-aggregation in solution to hexamers (insulin cannot bind to its receptors)
Pharm changes can help change structure
Zinc buffer/Protamination/A.A. substitution/pH changes/FFA/albumin
binding
- Insulin Factors to consider
o Onset of action (timing of admin)
o Peak affect (efficacy/hypoglycemia prediction)
Match up peak insulin action w/ peak glucose levels
o Duration of action (freq. of dose)
o Compatibility w/ other drugs
- Long-Acting Insulin Analogs (BASAL)
o Glargine/Detemir
o Activity/site independent
o Can also use NPH 2-3x/d
- Concentrated insulins
o Used in pts w/ extreme insulin resistance
o U-500 is 5x as concentrated as regular insulin; only available by vial
- Starting insulin for T2DM
o Fix fasting sugars first!
Start w/ 10 u/d & increase by 2-3 u/d until reach fasting target range (70-130)
o Prandial dosing 4-3-2 method (start w/ 4u, adjust every 3 days by 2u until hit target)

PATHOGENESIS OF T1DM
- ** Beta cell destruction resulting in life-long insulin deficiency **
- Prevalence doubling every 10 years
- T1DM-A
o Immune-mediated, gradual destruction of b-cells
o Islet-cell auto-antibodies = initial immune response
Initiates auto-immune effect & amplifies T-cell destruction
 Usually present in serum before/at time of diagnosis
o HLA-DR3 & HLA-DR4
HLA linkage responsible for ~40% total risk for diabetes
HLA Class II (DQ8/DQ2)
IDDM1 gene has autosomal dominant risk associated w/ diabetes
Usually polymorphisms of specific genes are associated w/ increased
risk for multiple autoimmune diseases [CTLA-4, IL-2a, 22 PTPN22]
o Chronic lymphocytic infiltration of islets (insulitis) w/ gradual b-cell destruction
o Pathogenesis
Genetic susceptibility
Loss of immunological self-tolerance
Islet APCs recognize non-conventional segments of the insulin
beta chain (9-23) which results in their activation
Insulin peptide fragments taken up by IAPCs, upregulation of MHC
genes & activation of T-cells & B-cells initiates process of islet
destruction (insulitis)
o Both CD4 & CD8 T-cells req. for insulitis, b-cell
destruction, & T1DM
Abnormalities in immune regulation
Environmental triggers
o 90% of pts w/ new-onset T1DM have NO FamHx!!!
Only 30-40% in identical twins
Still have an increased risk in families that already have hx of T1DM
o Environmental Triggers
Gut microbiome
Bacteroides dorei = increased risk
Actinobacteria/Akkermansia = protective (probiotics may be
protective!)
Enteroviruses ***Coxsackie virus (CBV-4) = STRONGEST LINK!***
CBV4 viral peptide cross-reacts w/ b-cell autoantigens
Virus acts as an amplifier!
Higher birth weight
Better to have early exposure to pathogens to develop immune system
o Autoantibodies
80% of children who develop DM have antibodies by age 3
ICAs, IAAs, GAD65, IA-2, ZnT8
DR3 = ICA+
DR4 = GADA+
Anti-peripherin = directed against Schwann cells w/in islets
89% of children who expressed >2 autoantibodies developed T1DM w/in 10
yrs of serum test
You can have ICA+ but that does not mean you will definitely develop DM
o Earlier onset of T1DM = more insulitis & fewer residual b-cells/insulin
Typically T1DM = <20y/o whereas LADA = 35-50 y/o [both can have
autoantibodies!]
 - T1DM-B
o Acute, direct viral destruction of infected beta cells or d/t the acute, innate anti-viral
immune response to infection
o Commonly triggered by enteroviruses [enteroviruses = major environmental
trigger in BOTH patterns]
Virus directly damages b-cells & induces apoptosis/cell death
OR innate anti-viral response to the infection is directly toxic to the b-cells
which induces apoptosis/cell death
NOTE: B-cell apoptosis results in release of specific nucleic acids &
proteins which can stimulate autoimmune processes (T1DM-A)
o No evidence of autoimmunity or HLA association, but more common in pts
w/ African American or Asian ancestry
o Higher mortality rate at onset
o Residual c-peptide & some intact functional b-cells
If pts survive initial onset, they usually have a more mild form of DM d/t
residual b-cells secreting small amt of insulin/c-peptide years after onset
- Genes related to immunity
o Innate Immune system genes (abnormal innate response failure to eradicate
virus chronic infxn)
IFIH1
PTPN22
TYK2
o Autoimmune genes (autoimmunity inflammation viral cytotoxicity loss of b-
cells & fxn)
HLA
Ins
- T1DM Prevention
o Primary = directed at any/all persons (vaccination?)
No trial to date has been able to successfully prevent DM in pts w/ ICA+
Currently attempting to use CBV-4 vaccines
o Secondary = initiate intervention in pt w/ ICA+ abs that has not yet developed overt
T1DM
DPT1 trial used insulin in ICA+ pts to down-regulate immune response
against b-cells
o Tertiary = reversal of b-cell destruction & induction of b-cell regeneration in pt w/
new onset T1DM
- Intensive Insulin Treatment
o Intensive exogenous insulin tx suppresses endogenous insulin secretion & this there
is less autoantigen expression can result in partial preservation of insulin
secretory capacity (c-peptide) for 18+months
Allows b-cells to rest, and some capable of b-cell redifferentiation

PATHOGENESIS OF T2DM
- Characteristics of T2DM
o Insulin resistance & hyperinsulinemia
o B-cell dysfunction
Impaired insulin expression & secretion
o Insulin deficiency
o Incretin deficiency
 Impaired insulin secretion
Enhanced glucagon secretion
- Rise in FBG levels over time d/t increasing insulin resistance, however FBG levels remain
relatively normal during pre-diabetic stage d/t over-secretion of insulin! (b-cells attempt to
compensate)
- Insulin resistance
o Impaired insulin-mediated glucose uptake in peripheral cells
o Impaired suppression of gluconeogenesis by liver
o Impaired suppression of lipolysis by adipocytes
- Obesity & associated risk
o BMI > 34.9 increases risk from 55% - 95%
o Visceral obesity often precedes development of insulin resistance & T2DM
more severe insulin resistance in pts who are viscerally obese
as visceral adiposity increases, level of insulin resistance also
increases
Cellular defects in insulin signaling, hypertrophic fat cells (increased FFAs), &
mitochondrial dysfxn all lead to insulin resistance
Also leads to impaired b-cell fxn & b-cell death!
o Lipotoxicity = accumulated FAs & metabolic products cause b-cell dysfxn, insulin
resistance, & T2DM
d/t ectopic fat deposition in insulin-target tissues
increased intramyocellular lipid content = increased insulin
resistance
many adipokines are diabetogenic (can directly inhibit insulin signaling
cascade!)
TNF-a & IL-6
Adipokines released by both visceral & ectopic fat!
TLR mediated release of pro-inflammatory adipokines/cytokines from insulin
target cells/tissues
Ectopically deposited FFAs bind directly to TLR-4 in adipose
tissue which triggers activation of a signaling pathways
leading to production of diabetogenic adipokines & cytokines
Adipokines/cytokines travel throughout body & directly cause insulin
resistance, while also upregulating TLR-4 expression in insulin-sensitive
tissues
- Insulin signaling defects
o Downregulation of insulin receptor number &/or affinity
o Downregulation of insulin receptor activation
Inhibition of receptor tyrosine/serine phosphorylation
o Downregulation of post-receptor signaling pathways
GLUT-4 metabolism, gene expression, etc.
Blocking docking PRs at receptor level, or blocking enzymes at levels of
signaling activation
- Insulin Deficiency
o Insulin secretory defects & impaired first phase insulin release
Pt can no longer compensate for insulin resistance
o Glucotoxicity
Adverse effect on insulin release from b-cells
Even minor increases in FBG levels dramatically interfere w/ b-cell ability to
release insulin
When FBG levels rise >100 mg/dL, first phase insulin release is
inhibited by at least 50%
 o Incretin effect
Incretins = gut-derived hormones that stimulate insulin release from b-cells
Incretin effect is diminished in T2DM
Reduced insulin secretion
Excessive glucagon secretion
o B-cell failure (exhaustion & death)
Pts w/ T2DM have significantly fewer b-cells
Significant increase in b-cell apoptosis in both obsess & lean T2DM
pts!
Glucotoxicity contributes to apoptosis in both populations
Lipotoxicity contributes in obese pts
Genetic vulnerability to stress-induced apoptosis in lean pts

T2DM CLINICAL APPROACH

- Legacy effect = weight loss, exercise, & rapid control of glucose levels at onset of
diabetes (T2DM) have long-term benefits w/ improved lifelong control & pts are at lower
risk for long-term complications
- Lifestyle modification on its own was better than metformin alone! (reduced risk of
develop. by 58% vs. 31%)
- Important to control glucose levels, HTN, & lipids
- Goal is to rapidly reduce glucotoxicity & lipotoxicity, and to preserved b-cell fxn
o Preserving b-cell fxn
Insulin, metformin, TZDs (PPARgA), GLP-1A, SGLT2 antagonists
o Major determinant of long-term success was mild (8-10lb) weight loss
o Most pts w/ T2D are insulin deficient w/in 7 years
- Staging DM
o Decompensated = HbA1C > 7.5%
Will not respond well to oral meds alone, req. intensive insulin tx x 3months
w/ additional drugs later
o Important to differentiate btw T1DM & T2DM after stabilization
Early insulin therapy req. with both forms
Look for anti-GAD & islet cell abs in T1DM
- ALWAYS START W/ METFORMIN!
- Insulin can be used in any stage of diabetes!
- Must consider numeracy literacy in pts for carb counting & insulin dosing
o V-Go delivers insulin in physiologic manner for 24 hours (can also have bolus fxn)
- Fibrates = affect both glucose absorption & gut microbiome
o FXR blocks glucose absorption in upper intestine
o TGR5 increases GLP-1 secretion
o can also lower LDL & A1c

T1DM CLINICAL APPROACH

- All daily activities impact glucose control!
 o Time req. for daily self-care ~90-180min/d
- Goals of tx are to maintain blood glucose as close to normal as possible & to prevent
complications, w/o inducing hypoglycemia
o Glucose control results in marked reduction in macrovascular risk & death
42% reduced risk for CV event
57% reduction in death d/t CV causes
o Target levels
FBG <100
RBG 81-160
2hrPP <160
HbA1C 6.5-7
- Self-glucose monitory w/ minimum of 4-6 BG checks/day
- Continuous glucose monitors helpful in analyzing patterns (4-10 min lag btw blood &
interstitial levels)
o Sensor inserted into subq tissue & measures glucose levels w/in interstitial fluid
o Basal dose set in meter
T1DM = 0.1-0.2 u/kg
T2DM = 0.4 u/kg
o Bolus doses must be calculated each time based on carb counting! (open loop)
Meal bolus dosing based on current BG & carbs to be eaten
Correction dose based on pts individual sensitivity to insulin (BMI is major
hint)
- Dosage calculations
o Insulin/Carb ratio = # of grams of carb that 1u of insulin will handle w/ a given meal
o Insulin sensitivity factor (ISF) = how much 1u of insulin will decrease BG
o Glycemic index = estimates total glucose excursion following consumption of
specific food
o Active insulin on board = calculates amount of insulin present from previous boluses
to prevent stacking of insulin!
Stacking often results in hypoglycemia d/t overtreatment
- Slightly increased basal rate at night = Dawn Phenomenon
- Potential complications of insulin pump therapy
o DKA if insulin infusion is disrupted for >2hrs, it can cause DKA w/in 3-4 hours
since there is no long-acting insulin on board
o Hypoglycemia may occur, but not as freq. w/ pump bc you can adjust throughout
the day
o Infusion site skin infections
o Weight gain (d/t decreased glucosuria = less calories lost in urine)
- Artificial pancreas & stem cell transplants will alter treatment in the future!!
o Pancreas transplants are standard medical care for T1DM pts w/ CKD
o Potential benefits of Islet cell & stem cell transplants
Potential cure of T1DM @ onset of dx rather than waiting until complications
occur
Restores normal fxn & QOL w/o monitoring/pumps/injections
o Islet cell transplants = req. 2 donor cadaver pancreases for adequate # of cells
Edmonton protocol (unfortunately short survival time for cells d/t rejection by
CD4 T-cells in liver)
Limited by source of adequate # of cells & site of implantation
o Stem cells
Immunologically inert potentially but they ended up facing same rejection
Using individuals own adult stem cells or embryonic stem cells
Insulin-like stem cells produced & placed in renal capsule (4 months of fxn)
DM COMPLICATIONS
- Macrovascular complications (large vessel dx)
o CV dx, cerebrovascular dx, peripheral vascular dx
Coronary artery dx, diabetic cardiomyopathy
Gangrene
Over 50% of all non-traumatic LE amputations d/t DM
Mesenteric vascular dx
- Microvascular/Neuropathic complications (narrowing of vessels/nerves leads to dysfxn d/t
oxidative stress)
o Diabetic Nephropathy
o Diabetic Retinopathy
o Diabetic Neuropathy

- Sustained hyperglycemia & induction of microvascular complications

o 1. Polyol Pathway
Sorbitol & fructose accumulation oxidative stress
o 2. Formation of Advanced Glycosylation End-Products (AGEs)
PR glycation leads to changes in tertiary structure
Glycosylation changes structure of collagen in vessels!
AGE-R activation of macrophages leads to more damage
o 3. Activation of PKC signaling pathway
- Glycemic Variability induces DM complications
o GV = freq/ glucose excursions outside normal glucose range (70-140)
o Fluctuations activate oxidative stress
- Diabetic Nephropathy
o DM responsible for 40% of all ESRD in US
o BP control very important (ACE/ARB)
o SGLT-2 inhibitors may have protective effects
- Diabetic Retinopathy
o Leading cause of blindness in USA
o Macular edema, cataracts. & glaucoma also issues
o Non-prolieferative vs. Proliferative
o Tx = photocoagulation or anti-VEGF-1
- Diabetic Neuropathy
o Peripheral sensory, peripheral motor, autonomic
o Peripheral Sensory = most common
Effects longest small nerve fibers first (toes/feet) then ascends symmetrically
Mild burning, tingling, itching, numbness, progressing to severe burning/knife-
like pain
o Autonomic neuropathy assoc. w/
Hypotension, tachy, loss of sweating, gastroparesis, diarrhea, neurogenic
bladder, impotency
- Diabetic foot
o Decreased sensation, peripheral dx, ischemia, glycosylation, all lead to
complications
o Infection, gangrene, ulceration, amputation
o Charcot Foot = major cause of below the knee amputations
Neuropathic osteoarthropathy of the foot
Excessive bone resorption, destruction, and deformity
Diabetic ulcers typical
- Skin
o Dermopathy & diabetic brown spots
o Necrobiosis Diabeticorum = thickening of blood vessel walls & endothelial cell
swelling
Interstitial mixed inflammatory cell infiltrate w/in dermis & lymphoid cell
aggregates deep
o Prayer sign (diabetic stiff hand syndrome)
Hands w/ thick, tight, waxy skin, limited joint range of motion & sclerosis of
tendon sheaths
o Dupuytrens contracture