2. Diabetes Mellitus
• Definition: Diabetes mellitus (DM) refers to a group of common
metabolic disorders that share the phenotype of hyperglycemia.
• Several distinct types of DM are caused by a complex interaction of
genetics and environmental factors.
5. Regulation of Glucose Homeostasis
•Balance b/n hepatic glucose production & peripheral
glucose uptake & utilization
•Insulin is most important regulator
•Other regulators: neural input, metabolic signals, other
hormones
•Fasting state: Low insulin levels
•Increase glucose production: hepatic gluconeogenesis
& glycogenolysis
•Reduce glucose uptake in insulin sensitive tissues
•Mobilization of stored precursors: AA & FFAs
6. Regulation of Glucose Homeostasis
•Glucagon : induced by low glucose & low insulin
•Stimulate glycogenolysis & gluconeogenesis by liver
and renal medulla
•Postprandial state:
•Illicit fall in glucagon & rise in insulin
•Insulin promotes storage of carbohydrate & fat &
protein synthesis
•Major postprandial glucose is used by skeletal muscles
•Other factors : skeletal myocytes (Irisin), adipocytes
(leptin, resistin, adiponectin), and bone
7.
8. Insulin Biosynthesis
•Insulin produced
•Beta cells of pancreatic islets
•Pre-pro-insulin : precursor polypeptide with 86 AA
•Pro-insulin:
•Structurally related to IGF I & II
•Binds weakly to insulin receptor
•Cleavage gives rise to C-peptide + A (21 AA) & B (30
AAs) chains of insulin
•C-peptide is cleared more slowly than insulin
•Amylin
•33 AA peptide co-secreted with insulin by beta cells
12. Epidemiology
•IDF report: 592 individuals will have DM by the year
2035G.C
•Prevalence of type 2 DM increasing due to
•Increasing Obesity & decreased activity
•Countries with the greatest number of individuals with
DM in 2013
•China( 98.4 mil),India(65.1 mil),USA(24.4mil),Brazil
11.9mil),Russian Federation (10.9mil)
•80% 0f diabetics live in low-middle income countries
•DM increases with age
•WW most people with DM are b/n the age of 40-59 years
13.
14. Classification
• Based on pathogenic process that lead to hyperglycemia
• Two broad categories
• Type 1 & type 2 diabetes
• Both are preceded by a phase of abnormal glucose
homeostasis
• Type 1 DM :
• Complete or near- total insulin deficiency
• Type 2 DM:
a) variable degree of insulin resistance
b) Impaired insulin secretion
c)Increased glucose production
15.
16. •Type 2 DM is markedly increasing among overweight
children and adolescents.
• Some individuals with phenotypic type 2 DM present
with DKA but lack autoimmune markers and may be
later treated with oral glucose-lowering agents rather
than insulin (have been termed ketosis-prone type 2
DM).
• some individuals (5–10%) with the phenotypic
appearance of type 2 DM do not have absolute insulin
deficiency but have autoimmune markers) suggestive of
type 1 DM (termed latent autoimmune diabetes of the
adult).
17. •LADA-late onset auto immune diabetes of adults
(type 1)
•Age >30yrs, more likely to be <50yrs
•Immune markers for type 1 present (ICA, GAD
autoantibodies)
•personal or family history of other autoimmune
disease.
•Respond to oral agents early phase,more likely to
require insulin treatment within 5 years
•Complete B-cell destruction over 2-3yrs
•Usually lean body wt(normal BMI)
18. Classification Cont…
• Maturity-onset diabetes of the young (MODY) and
monogenic diabetes
• are subtypes of DM characterized by autosomal
dominant inheritance
• early onset of hyperglycemia (usually <25 years;
sometimes in neonatal period)
• and impaired insulin secretion
19. •Others causes are
•Mutations in insulin receptor
•Pancreatic exocrine disease
•Cystic fibrosis related DM
•Endocrinopathies: Acromegally, Cushing disease
•Viral infections
•Drugs: Glucocorticoids
20. Gestational DM
•Glucose intolerance developing during pregnancy
•Most women revert to normal glucose tolerance
postpartum
•Risk of DM in the next 10-20years : 35-60%
•If diagnosed in early prenatal visit: “Overt” DM
22. Pathophysiology…Type 1 DM
• Interaction of Genetic, Environmental, & auto-immune factors
• Several factors characterize type 1 DM as auto-immune
condition
• Association with genes of MHC/HLA
• Presence of Islet cell specific auto antibodies
• Frequent occurrence of other auto immune diseases
• 85% of patients have circulating islet cell auto antibodies(
ICA), Anti Insulin( IA), Anti Glutamic Acid Decarboxylate (
Anti-GAD).
• Excessive secretion of Glucagon
23. Pathogenesis of type 2 DM
•Insulin Resistance
•Increased hepatic Glucose production
•Decreased Insulin mediated Glucose
transport
•Impaired beta cell function
•Hyperglycemia + Hyperinsulinemia leads to
Glucose toxicity & lipo toxicity to beta cells
24. Screening
• Widespread use of the FPG or the HbA1c as a screening test for
type 2 DM is recommended because
(1) a large number of individuals who meet the current criteria
for DM are asymptomatic and unaware that they have the
disorder,
(2) epidemiologic studies suggest that type 2 DM may be
present for up to a decade before diagnosis,
(3) some individuals with type 2 DM have one or more
diabetes-specific complications at the time of their diagnosis,
(4) treatment of type 2 DM may favorably alter the natural
history of DM, diagnosis of prediabetes should spur efforts for
diabetes prevention.
25. Screening
•Indications for screening ADA recommendation
•Age >45 years every 3 years
•BMI >25kg/m2 plus one additional risk factor
•No need of screening for type 1 DM
•Rare long asymptomatic period
28. Diagnosis
Three broad categories of glucose tolerance
Normal: FPG<100mg/dL,2-H
PPG<140,HbA1c<5.7%
Impaired:FPG=100-125mg/dL,2-H
PPG 140-199mg/dL,HbA1c 5.7-6.4%
DM: FBS>=126mg/dL, 2-H
PPG>=200mg/dL, HbA1c>=6.5%
29. Approach TO DM patient
•Hx
•Family hx of DM & its cx
•Wt change
•Risk factors for CVD
•Exercise, alcohol use, smoking, nutritional hx
• Symptoms of hyperglycemia
• polyuria, polydipsia, weight loss, fatigue,
weakness, blurry vision
•Frequent superficial skin infections (vaginitis,
fungal skin infections),
•Delayed wound healing after minor trauma
30. •If known DM
•type of Rx
•Level of gycemic control-Hgb A1c,FBS
•frequency of hypoglycemia
•Diabetic cx
•pt’s knowledge about DM, exercise, and
nutrition
•DM-related comorbidities -
HTN,CVD,dyslipidemia
31. •P/E- complete+ special attention on
•BMI
•BP –supine & sitting, orthostatic blood pressure -AN
•> 140/90 mmHg is considered HTN in DM.
•Oral hygiene, teeth and gums, periodontal disease is
more frequent
•Peripheral pulses
•Extremities
•Callus, nail disease
•Fungal superficial infections, ulcer, fissures
•deformity ( hammer or claw toes and Charcot foot)
•Injection sites
•retinal examination
•peripheral neuropathy
•ankle reflexes
• Vibratory sensation, touch with a monofilament,
pinprick sensation
32. • Classify the type of DM
• Laboratory Assessment
• To meets Dx of DM-FBS,RBS,OGT
• level of glycemic control HgA1C.
• screened for DM-associated conditions or Cx
• U/A-protein- microalbuminuria
• Lipid profile---dyslipidemia,
• TFT---------thyroid dysfunction
• Cardic stress test—if CVD risk.
• laboratory test help in classification of the type of DM
• Serum insulin or C-peptide - do not always distinguish type 1 from type 2
DM,but
• low C-peptide level confirms a patient's need for insulin.
• Many individuals with new-onset type 1 DM retain some C-peptide
production.
• islet cell antibodies at the time of diabetes onset may be useful if the type of
DM is not clear based on the characteristics described above
33.
34. Dx of GDM
•“One step” 75 gm of anhydrous glucose (1 H+2 H )
+FBS
•FBS>=92mg/dL
•1 H >= 180mg/dL
•2 H >=153mg/DL
•“Two Step Test” 50gm glucose followed by 100gm(
fasting)
•FBS> 95mg/dL
•1 H BG> 180mg/dL
•2 H BG >155mg/dL
•3 H BG> 140mg/dL
35. Management of DM
•Supportive Treatment
•Pt education
prevention - diet,exercise
SMBG, urine ketone
Mx during acutes illnesses
Mx of hypoglycemia
foot & skin care
Mx b/n ,during & after exercise
modify risk factors
36. •Exercise
• ↓CVS risk ,↓BP,↓body fat,↓blood glucose
• Maintain muscle mass
• Increase insulin sensitivity
• Can lead to hyper/hypoglycemia based on
• Pre exercise glycemic level
• Pre exercise insulin level
• Extent of exercise
• Monitor RBS before, during & after ex.
• Delay if RBS <100mg/dl or >250
• Eat meal 1-3hr before ex. Or take supplemental CHO
atleast every 30min.
• ↓insulin doses
• Avoid injection of insulin to the exercising limb
42. Thiozolidinediones
•Insulin sensitizers that reverse cellular defects
underlying the insulin resistance
•increased insulin-stimulated glucose uptake by
skeletal muscle cells
•Decrease hepatic glucose production
•Increase efficiency of β-cells and prolong β-cell
survival
43. Biguanides
•Metformin
•Decline in circulating insulin levels since no beta
cell stimulation
•Weight loss or no weight gain
•Only diabetic medication shown to reduce
macrovascular risk
•39% reduction in the risk of MI, 30% reduction in
all macrovascular endpoint
44. Sulfonureas
•Bind to SU receptors on the surface of pancreatic
beta cells leading to a closure of voltage
dependent KATP channels.
•This causes cell membrane depolarization,
calcium entry into the cell and insulin secretion
•This allows for insulin release at lower thresholds
than normal
