Diabetes mellitus

Definition:
Syndrome of disturbed metabolism and inappropriate hyperglycemia secondary to absolute or relative deficiency
of insulin, or a reduction in biological effectiveness of insulin.
Classification of diabetes mellitus
Type 1 DM Type 2 DM Gestational DM Other types
nd rd
IDDM NIDDM Developed in 2 , 3 trimester -Pancreas (acute/chronic
of pregnancy. pancreatitis- cancer)
Usually improved after -Endocrine (Cushing’s $-
delivery thyroid dysfunction-
Types of type 1 Risk factors: acromegaly-
A: immune mediated 1. >25yrs pheochromocytoma)
(commonest) 2. Positive family history -Liver (NAFLD- liver
B: idiopathic 3. Previous history of cirrhosis)
C: LADA: latent autoimmune GDM -Drugs (ß blockers- thiazide-
diabetes in adults 4. Previous birth of steroids- statin)
macrosomic baby -Genetic (down- Klinefelter-
5. Obesity turner- wolfram”
6. steroid DIDMOAD”- defect of ß cell
Causes: Causes: Diagnosis of GDM “MODY”)
*Immune-mediated ß cell *Insulin resistance with After OGTT of 75gm
destruction relative insulin deficiency -FBG > 92mg/dl.
-1hP.P > 180mg/dl.
-2hP.P > 153 mg/dl.
Difference between type1 DM and type2 DM:
Type 1 DM Type 2 DM
Risk factors 1) Positive family 1) age>40 yrs.
history 2) Metabolic syndrome x
2) Autoimmune 3) 1st degree relative with
disease diabetes
4) IGT, IGF
5) Hyperuricemia
6) Acathosis nigricans.
Onset <30 yrs. >40 yrs.
Except LADA
Epidemiology 5-10% of all diabetes 90% of all diabetes
Etiology & *ß cell destruction *Peripheral insulin resistance
pathophysiology causes: autoimmune, *↑ hepatic glucose production
genetic, environmental
factors
Genetics Monozygotic twin Monozygotic twin
30-40% 70-90%
HLA class II DR3 and Non-HLA associated
DR4
Auto antibodies Pancreatic islet cell Ab
(PICA), anti-glutamic
acid decarboxylase Ab
(GAD).
Body Habitus Patient Normal to thin Typically, overweight with
increased central obesity
Insulin Life style modification & diet
therapy. Oral hypoglycemic
therapy + insulin.
 N.B:
Normal level Criteria of diagnosis Criteria of diagnosis Target glycemic
Pre-diabetes Diabetes control
FBG<100 Mg/dl FBG: 100-125 Mg/dl FBG>126 Mg/dl FBG: 80-130 Mg/dl
2hr pp < 140 2hr pp: (OGTT 2hr pp > 200 Mg/dl 2hrs pp< 180 Mg/dl
Mg/dl by75mg) 140-199 HbA1C > 6.5% Hb1c< 7 %
HbA1C < 5.7% Mg/dl Random blood sample:
HbA1C: 5.7-6.4% > 200 Mg/dl + hyperglycemic
symptoms
polyuria, polydipsia, polyphagia,
weight loss, blurry vision
N.B: repeat confirmatory test for
diagnosis
Actions of Insulin
 Complications
Acute Chronic GIT Ocular Skin
*Hypoglycemia A. Non vascular complications (e.g., 1. Tongue fungal 1. Errors of *see below*
*DKA infection, gastroparesis) infections: white refraction.
*Hyperglycemic B. Vascular complications: further tongue. 2. Cataract.
hyperosmolar divided into 2. Teeth: loose with 3. Rubeosis iridis.
state Microvascular: Macrovascular dental caries. 4. Argyll Robertson
1. Retinopathy, large vessels due to 3. Delayed gastric pupil
2. Nephropathy atherosclerosis emptying (gastro 5. Ophthalmoplegia.
3. Neuropathy, which is extensive paresis). 6. Lack of
in DM: 4. Chronic accommodation to
1. Peripheral cholecystitis& gall dark.
Vascular Diseases bladder stones. 7. Recurrent eye
2. coronary artery 5. NAFLD infections
diseases (especially in
3. Cerebrovascular metabolic
diseases syndrome).
Neuropathy: 6. Nocturnal
Focal diffuse diarrhea alternating
1.Mononeuropathy 1. Autonomic with constipations.
or multiple neuropathy
mononeuropathy 2. Distal
2. Radiculopathy, symmetrical
plexopathy sensorimotor
polyneuropathy
 Complications of skin
*Metabolic *vascular *associated with diabetics *Iatrogenic Skin
1. Acanthosisnigricans: 1. Diabeticdermopathy: Vitiligo Insulin allergy
-Hyperpigmented velvety -Most common Lichen planus Lipoatrophy: with
papillomatous overgrowth of the dermatological manifestation necrolytic migratory loss of SC fat, less
epidermis. of DM. erythema: common with purer
-common in flexures -bilateral well-circumscribed, insulin formula.
-causes: hyperinsulinemia, insulin atrophic, brownish scars Lipohypertrophy: as
resistance -common in the chin of the soft, subcutaneous
2.skin tags tibia nodules or thickening
3. Bullosisdiabeticorum (Micro vasculopathy) at sites of repeated
-lower limbs Common in males> 50 yrs. injections.
-common in elderly 2. Rubeosis faciei:
4. Necrobiosis lipoidica dibeticorum -chronic flushed appearance in
-chronic granulomatous skin lesion the face and neck of people
-common in the chin of the tibia with diabetes
-common in females -The condition may get
Early: erythematous well worsen by caffeine & alcohol.
demarcated lesion. 3. Periungual telangiectasia:
Late: yellow thin atrophic center -dilatation of proximal
with shiny Surface nailfold capillaries.
5. Diabetic sclerodema 4. Lower limb abnormalities
-thickening of the skin, post.aspect with vascular changes
of the neck, upper part of back, face, -erysipelas
acral areas 5.Calciphylaxis:
6. Yellow skinandnails: Small vessel vasculopathy
(carotenemia) occurs in renal failure
Common in skin and nails
 Acute complications
hypoglycemia DKA
Blood glucose level <70mg/dl Most common
1st presentation of type 1 DM
Etiology Etiology
1.Missed meal. 1.Missed insulin
2.Over dose of insulin 2.Stress (emotional- infection-surgery- trauma- pregnancy- delivery)
3.↑ exercise. 3.Starvation
4.MI, stroke
Manifestations Clinical picture
A: neurogenic 1.hyperglycemia→ (glucosuria- polyuria-polydipsia-dehydration)
Tachycardia (tachycardia/hypotension)
Sweating 2.ketonemia (abdominal pain, tenderness, anorexia, N,V)
Tremors 3.acetone breathing, kussmaul respiration
Anxiety 4. electrolyte disturbance (↑k→↓k) (↓Na)
Palpitations 5.coma: (dehydration, acidosis, electrolyte disturbance)
Cold extremities 6.death: (dehydration, acidosis, electrolyte disturbance, cardiac arrest)
B: Neuro glycopenic
Hunger Investigations
Pain *glucose:> 300Mg/dl
Blurring of vision *ABG: metabolic acidosis ↑ anion gap
Fits *electrolytes: (↑k→↓k) (↓Na, ↓p)
Dizziness *serum ketone bodies: ↑
Confusion *serum creat. , BUN ↑
Coma *serum osmolality ↑
*urine analysis (ketone bodies, glucosuria)
*ECG to exclude MI
Treatment Treatment
Glucose: 1.treatment of the cause
Conscious: oral 2.fluid
Unconscious: IV glucose 25%/ 1Mg glucagon SC *normal saline (15-20ml/kg/hr) guided by CVP, UOP
* when BG< 250→ glucose saline infusion
* K to correct electrolytes
* insulin infusion (to correct acidosis not hyperglycemia)

Complications
1.hypovolemic shock dehydration.
2. Vascular thrombosis.
3. Pulmonary edema → fluid therapy.
4. Cerebral edema →rapid ↓of blood glucose.
Hyperglycemic hyperosmolar state
 Diabetic peripheral neuropathy (chronic)
classification
Focal diffuse
1.Mononeuropathy or multiple 1. Autonomic neuropathy
mononeuropathy 2. Distal symmetrical sensorimotor
2. Radiculopathy, plexopathy polyneuropathy

Risk factors Proposed hypotheses of diabetic PN:

1. Duration of diabetes. 1. Chronic hyperglycemia
2. Poor glycemic control. 2. Nerve microvascular dysfunction
3. Retinopathy. 3. Increased free radical formation
4. Old age. 4. Polyol pathway hyperactivity
5. Albuminuria. 5. Protein kinase C hyperactivity
6. Vascular risk factors. 6. Non‐enzymatic glycation “AGEs”
7. Abnormalities of nerve growth

Diffuse
a-Distal symmetrical sensorimotor polyneuropathy
-most common
-Occur in children
-Sensory manifestations are the commonest (bilateral-ascending- symmetrical) foot before hand
 Clinical picture
Symptoms signs
Positive symptoms Negative symptoms Sensory motor
1. Pain (pricking, 1. Hypoesthesia Superficial deep *Inspection
burning, stabbing, “numbness” pain→ pain prick 1. Vibration sensation: wasting muscle
lancinating), especially 2. Anesthesia “loss of temperature→ test tuning fork 128 HZ. *Testing motor
at night. sensation” [In Stocks & tube 2. Joint sense & power
2. Paresthesia (abnormal gloves pattern] light touch→ cotton movement. *ankle/ knee
unpleasant sensation, e.g. 3. Unsteadiness during 3. Nerve sense. reflexes
tingling) walking “late”If sensory 4. Romberg sign.
3. Allodynic sensations ataxia developed 5. Ankle reflex
(severe pain due to non
painful stimulation, e.g.
contact clothes)
4. Hyperesthesia
(exaggerated touch
sensation)
5. Hyperalgesia
(exaggerated pain
sensation)
Complications
1. Recurrent injuries with loss of protective sensations. 3. Charcot arthropathy.
2. Neuropathic foot ulcers 4. Unsteadiness & recurrent falls.

Screening diabetic neuropathy

Type1→ after 5 yrs. Type2 → at diagnosis
Then annual
Management
Pharmacological: ( 1st line)
Anticonvulsant: Pregabalin, Gabapentin.
TCA : amitriptyline
SSNRI: duloxetine
Alpha-lipoic acid
Topical capsaicin:
Opiates:
IV lignocaine
b-Autonomic neuropathy
1. Cardiovascular
a. Reduced Heart Rate
Variability.
b. Resting tachycardia.
c. Orthostatic hypotension.
d. Ischemic symptoms
unawareness
5.Distal
hypohydrosis/anhidrosis,
Gustatory sweating &
hyperhidrosis in face, neck
2.Gastrointestinal
a. Diabetic gastroparesis
(gastropathy);
Postprandial Bloating,
fullness, nausea, vomiting.
b. Constipation, nocturnal
diarrhea.
c. Biliary dyskinesia.
6. Hypoglycemia
unawareness.
Non Pharmacological:
TENS
3. Urogenital 4.Sudomotor dysfunction
*neurogenic bladder
*urinary retention
*Erectile dysfunction
7. Abnormal pupillary 8.Edema of the feet and
function: delayed legs and burning hot feet
accommodation to dark, at night due to altered
blurred vision. vasomotor tone.
 Focal
Mononeuropathy or multiple mononeuropathy Radiculopathy, plexopathy
rapid onset, reversible, Truncal Radiculopathy:
more in men with advancing age. Affect 30% of diabetics.
cranial neuropathies: Acute onset pain in a dermatomal distribution over the
Especially oculomotor: ptosis , ophthalmoplegia on thorax or the abdomen.
double vision after lid elevation, pupil mostly spared. Pain is asymmetrical, may increase with cough or
Abducent: ophthalmoplegia on double vision, sneezing.
convergent squint. Recovery occur in most cases.
Facial: bell’s palsy. Plexopathy :
entrapment neuropathies: Femoral neuropathy “diabetic amyotrophy”
median nerve. The patient presents with severe pain, which is felt
Ulnar nerve. deep in the thigh with progressive asymmetrical
Lateral cutaneous nerve of the thigh. proximal leg weakness and atrophy of quadriceps.
Peroneal nerve. MRI studies of lumbosacral spines is mandatory to
exclude focal nerve root entrapment.
 Diabetic nephropathy (chronic)
Stages:
1. Elevated glomerular filtration rate with enlarged
kidneys
2. Intermittent Microalbuminuria
3. Microalbuminuria
4. Proteinuria and Nephrotic syndrome.
5. ESRD

Risk factors Screening TTT

1. Genetic factors for HTN Creatinine annually *control diabetes, HTN
2. FH of diabetic nephropathy Micro albuminemia *avoid nephrotoxic drugs
3. Poor glycemic control *albumin/creatinine ratio (24hrs *protein restriction
4. Black races urinary protein excretion) *ACEI, ARB
5. Smoking * Dipstick (1st line for protection of heart,
correct Micro albuminemia)
Features suggestive of non-diabetic kidney disease
1. Absence of retinopathy
2. Short duration (<5 years) of diabetes,
3. Rapid progression of renal dysfunction (fall in eGFR >15 ml/minute per year),
4. Onset of proteinuria without a history of microalbuminuria
5. Haematuria
6. Systemic features of other diseases e.g. vasculitis.

Treatment
N.B: Target glycemic control
FBG: 80-130 Mg/dl
2hrs pp< 180 Mg/dl
Hb1c< 7 %
goals of diabetes include:
1. Prevention of complications through achievement of target glycemic control. (Especially macrovascular
complications)
2. Treatment of associated complications and risk factors.
3. Target glycemic control of diabetics
Methods of blood glucose monitoring:
1-HbA1c
• 2 times a year → stable glycemic control
• quarterly→ patients who are not meeting their glycemic control
2-Self-monitoring blood glucose(SMBG)
• All patients especially treated with insulin
• pre meals, at bed time , at time risk of hypoglycemia
 3-Continuous blood glucose monitoring (CGM)
• type 1 young patients
• Diet & exercising programs
• Weight loss especially abdominal obesity, decreases insulin resistance
Medical treatment of hyperglycemia
Antidiabetic medications:
1. Medications to help overcome insulin resistance or insulin sensitizers (e.g., biguanides, thiazolidinediones
[TZDs]).
2. Medications to help with the β-cell defect (e.g., sulfonylureas, meglitinides/ amylin analogs, incretin mimetics,
dipeptidyl-peptidase 4 [DPP-4] inhibitors).
3. Medications that target the reabsorption of glucose (e.g., sodium-glucose cotransporter-2 [SGLT-2] inhibitor).

1-Biguanides
Initial choice for newly diagnosed
patients with insulin resistance
Its action is independent on B cells. ( no
hypoglycemia risk).
mechanism 1. ↓ hepatic glucose production.
2. ↓ absorption of glucose from
intestine.
3. Improving insulin sensitivity by ↑
peripheral glucose uptake and
utilization.
2-TZDs
Pioglitazones, rosiglitazone
rosiglitazone → ↑the risk of MI.
1.ligands that bind to and activate peroxisome proliferator–activated
receptors (PPARs).
2. ↑insulin-stimulated glucose uptake into skeletal muscles, &
peripheral tissues.
3.modest ↓in blood pressure, enhanced fibrinolysis, and improved
endothelial function
 4. Assist in wt. loss. ( weight neutral).
Side effects 1. Anorexia, nausea, dyspeptic
symptoms, bloating, diarrhea, cramps,
may vitamin B12 deficiency.
2. Avoided in patient with renal
impairment (lactic acidosis) with e GFR
< 30 ml/min.
3. Used with caution in elderly (above
80y), patient with hepatic impairment,
& metabolic acidosis.
3- SGLUT-2 inhibitors
Canagliflozin (Invokana), empagliflozin (Jardiance), and dapagliflozin (Farxiga)
mechanism
1. SGLT-2 →sodium-dependent glucose transporter protein located
in the PCT in the kidneys.
2. responsible →90% of glucose reabsorption.
3. inhibition of SGLT-2 →an ↑in renal glucose excretion, →↓
plasma blood glucose levels.
4. ↑ insulin sensitivity, ↓ gluconeogenesis, and improve insulin
secretion from pancreatic β cells.
5. modest weight & blood pressure reduction.
6. ↓ the risks of cardiovascular mortality, hospital admission for
heart failure, it causes slower progression of kidney disease in
patient with type 2 diabetes at high cardiovascular risk.
4. preserve pancreatic β-cell function
1. Weight gain (time- and dose-dependent)
2. Fluid retention,
3. Heart failure, (Blackbox warning for use in patient with CHF).
4. ↓ bone density & ↑fracture risk,(postmenopausal women)
5. increased bladder cancer risk.
Side effects
1. patients with severe renal impairment (eGFR < 45).
2. vaginal yeast infections and urinary tract infections, especially
in women.
3. ↑in both LDL and HDL cholesterol,
4. ↑of bone fracture, FDA Blackbox warning with ↑ risk of
amputation. (canagliflozin)
5. possible risks of liver damage, breast cancer and bladder
cancers (dapagliflozin only).
6. Not used in type 1 (euglycemic DKA)
 4-Incretin mimetics
Gut derived hormones released in response to food released from the terminal ileum
DPP4 inhibitors: GLP-1 analogues:
sitagliptin, saxagliptin, linagliptin, alogliptin, Exanatid (Byetta) or long acting (Bydureon). Liraglutide
vildagliptin (Victoza). Dulaglutide (trulicity). Lixisenatide
(Lyxumia).Albiglutide
SQ injection daily or weakly
mechanism slow the inactivation of incretin hormones with low 1.Analogue of GLP-1 →resists degradation by endogenous
hypoglycemic risks and less weight gain Dpp-4, enhancing glucose stimulated insulin release, ↓the
release of glucagon after meals, delaying absorption of
nutrients, and causing the sensation of satiety.
2. Modest weight loss effect with satiety
Side effects 1.fewer side effects as this group is well tolerated. 1.GIT upset, N,V, diarrhea, dizziness, headache. ( avoided
2.used with caution in patients with heart failure. by slow titration).
(higher risk of hospitalization for heart failure with 5. Potential risk of pancreatitis
saxagliptin only).
3.dose modification in renal failure.
4.Potential risk of pancreatitis
5- Insulin secretagogue
A. Sulphonyl urea: B. Glinides:
glipizide, glyburide, and glimepiride, glibenclamide, Repaglinides , nateglinides
gliclazide
mechanism these drugs bind to the sulfonylurea receptors on the β these drugs similar to sulfonylurea
cells →the closure of voltage-dependent potassium (ATP) ↑insulin secretion from the pancreatic β
channels. cells with shorter duration of action.
 facilitates cell-membrane depolarization→ calcium entry at meal times→improve prandial insulin
into the cell, and subsequent insulin release. release, ↓postprandial hyperglycemia.
Side effects 1. Hypoglycemia 1. Hypoglycemia (less than SU)
2. Weight gain. 2. Used with caution in patients with
3. Used with caution in patients with renal and hepatic renal and hepatic impairment.
impairment.

6. glucosidase inhibitors: 7.Amylin analogue

Acarbose, miglitol
Mechanism 1.slowing the absorption of carbohydrates
from the GIT.
2.inhibit the enzyme in the small intestine
breaking down disaccharides and
complex carbohydrates, delaying their
absorption and attenuating postprandial
blood glucose elevations.
Side effects Abdominal discomfort, flatulence, and
diarrhea
Pramlintide
Amylin is a hormone that is Co secreted with
insulin by the pancreatic β cells. It regulates
glucose levels by suppressing glucagon release,
delaying gastric emptying, and possibly
reducing appetite.
it has been shown to reduce postprandial blood
glucose excursions, improve weight control
1. Cause severe hypoglycemia when combined
with prandial insulin (dose must ↓ by 50%).
2. Used with caution in patient with
gastroparesis, or unable to sense hypoglycemia
 Insulin therapy
Indications Insulin regimen:
1. Type 1 DM. 1. Multiple daily injection regimen (basal-bolus therapy )
2. Type 2 DM that fails to achieve control after diet and OHT. Basal of intermediate or long acting (NPH or levemir or lantos)
3. Patient with diabetic complications. once daily & Boluses pre meals of rapid or short acting insulin
4. Diabetes during pregnancy. (regular, lispro, glulisin).
5. DKA. 2. Split mixed regimen:
6. Diabetics with stressful situations such as: severe infections- The use of pre mixed insulin (mixtard ;regular+ NPH) in 2 daily
surgery –trauma. injections 2/3 dose before breakfast ,1/3 before dinner.
7. As initial therapy To control the process of glucotoxicity 3. Continuous Subcutaneous Insulin Infusion (CSII)
especially in patient who are newly diagnosed with very high Needs accurate regular meals Timing (risk of hypoglycemia)
FBG and Hba1c

N.B
↑weight neutral ↓weight

TZDs (5-6 Kg) Metformin GLP (2-3KG)

Sulphonyl urea DPP4I
Insulin (2-4 Kg) α glycosides inhibitor SGElt2

Amylin (1-1.5Kg)

Renal impairment:
XCI (metformin, SGUI)