This document discusses type 2 diabetes, including its definition, pathogenesis, and current state of understanding. It defines type 2 diabetes as a group of metabolic disorders characterized by hyperglycemia due to defects in both insulin secretion and action. The document notes that type 2 diabetes is increasing worldwide and can now affect adolescents. It discusses the genetic and environmental factors involved in its pathogenesis, including islet cell defects and insulin resistance in tissues. While lifestyle changes and current pharmacotherapies can help manage the disease, the document concludes that the underlying mechanisms remain poorly understood and that type 2 diabetes continues to represent a major global health challenge.

1. Dr. Assem A. Zeyada M.D.
Emeritus Professor of Internal
Medicine
Consultant of Endocrinology
Cairo University & Hospitals
Do We Know What Is
Type 2 Diabetes?

2. Definition
Diabetes, Hyperglycemia or Something
else?
Diabetes (G) = Siphon, meaning diarrhea of the Kidneys
Mellitus (G) = Honey like

3. Joslin 1916
we need standards for diagnosis of diabetes
Fajans 1978
Diabetes should be considered as a heterogeneous
group of disorders affecting carbohydrate protein
and fat metabolism due to relative or absolute
insulin deficiency with specific microvascular
complications and high incidence of macrovascular
complications
ADA 1997
A group of metabolic disorders characterized by
hyperglycemia due to defects in insulin secretion
and or action with consequent long term damage,
dysfunction and failure of various organs

4. Type 2 Diabetes
2015
Where are we?
The Plague of the century
The Global burden for governments
economy worldwide
The Ghost we are fighting

5. Incidence and prevalence are increasing
tremendously worldwide
Previously a disease of adults, is creeping to
adolescent and late childhood (linked to pubertal
growth)
The Plague Of The Century

6. Insidious onset with transition from prediabetes to
diabetes within years according to prediabetes definition
20-30% of prediabetics in the stage of IFG or/and
IGT suffer microvascular, neuropathic and macrovascular
complications
Diabetes commonly remains asymptomatic for variable
period (usually few years). Diagnosis may be made under
the following conditions:
The Ghost we are fighting
When Symptoms become florid Or
Occurrence of diabetes-specific complications Or
Different settings of clinical scenarios Or
Routine check up
Selective population-based screening is cost effective but is
not feasible

7. Pathogenesis
Genetic/Environmental
Islets defect Insulin Resistance

8. Genetic/Environmental

9. Despite Herculean efforts, single nucleotide
polymorphisms (Diabeto SNPs)exceed 30 and most are
unknown . Many ethnic groups are not yet studied
In conclusion: Robust Genetic Prediction and personalized
Diabetes Intervention remains a distant hope
With time many deleterious factors are identified which
empower the continuity of the plague
Long Term Exposure to traffic related air pollution in
healthy physically active and non smokers; contributes to
the development of Diabetes
Anderson Z, J Raachou-Nielsen O et al
Diabetes Care 2012;35:92-98
Genetic Basis
DAGOGO-JACK S.Commentary
Diabetes Care 2012;35:193-195
Environmental Hazards: beside unhealthy life style

10. Islets of Langerhans
 α-Glucagon
 β- Insulin
 δ- SMS
 PP: Pancreatic
polypeptide
 ε- Ghrelin

11. Islets Defect

12. Islet Dysharmony
 Islet paracrinopathy:
sensitivity of α-cell to
endogenous insulin
hyperglucagonemia
 Many yet unknown
During the show many come into the play e.g
hypertension, Dyslipidemia, mitochondrial
dysfunction, oxidative stress and amyloid
Islets in Type 2 DM
β - Cell mass
 Programmed in
utero
 Apoptosis exceeds
neogenesis
 Islets derived
cytokines
β - Cell defect
 programmed in
utero
- AIR
- Lost 1st phase
insulin secretion
- Diabetes

13. Acute Insulin Response Vs Proinsulin Level
Cumulative incidence of DM: Prospective study for 27 years over
children with +ve FH of Type 2
AIR
(pmol/L)
Proinsulin
(pmol/L)
T1 < 282
T2 282 – 456
T3 > 456
< 1.7
1.7 - 3.1
> 3.1
Zethelius B. et al Diabetetologia 2003; 46 : 20 - 26

14. Insulin resistance

15.  Starts many years before the onset of abnormal glucose
tolerance possibly traced to genetic and embryonic
programming
 Beside poorly understood mechanisms, the primacy and
supremacy of skeletal muscle, liver and adipose tissue remains
extremely controversial
 Anywhere insulin resistance starts, the resulting
hyperinsulinemia and finally hyperglycemia induce insulin
resistance in all insulin-sensitive tissues and perpetuation
continues
 Chronic inflammatory process is a common associate and
augment the whole cascade

16. Hyperinsulinemia
Hyperglycemia
FFA
Interleukins
Mitochondrial
Dysfunction
Intracellular
fat
Defective
Glycogenesis
Diabetes Care November 2009; 32: suppl 2
NAFLD
&
insulin action & insulin clearance
HGP & Lipolysis
TNF-a
Atherogenic
dyslipidemia

17.  Healthy diet and calorie restriction aiming at B.wt
reduction especially in obese
 Increased physical activity. Beside helping body weight
reduction is beneficial regarding depression and dyslipidemia
Self Management Diabetes Education (SMDE)
 considered now the gold standard , but handicaps are
many with increasing life stresses
Pharmacotheray
 The ideal drug(s) is still unknown. Metformin remains the
best and the denominator for all drug combinations
Bariatric Surgery
 When indicated for the proper patient , proved effective in
improving diabetes and other CVRs
In Management
Life Style Modification

18. Extra pancreatic
Type 2 D.M
Where are we ?
Pancreatic
 A circus initiated by
localised autoimmune
process and induced
by epitopes from
apoptotic B-cells
 Determined genetically
and by intrauterine
environment
Hypothalamic Incretin Defect
Imbalance between Unidentified
Orexigenic and defect(s) in
Anorexigenic GIP-1 system
centres

19.  Type 2 diabetes is a state of hyperglycemia emanating from
islet dysfunction and insulin resistance which occur early in life
and progress steadily. The mechanisms behind both are poorly
understood
 Alternatively it may represent a component of dysmetabolic
syndrome again of unknown nature
 For the moment no ideal therapeutic approach exists and
chronic complications continue
 Still gloomy. We are facing an epidemic with enormous human
suffering and economic costs
 Lessons from UKPDs, Accord, ADVANCE, VDAT and others
advocate early intervention at the onset or even before
hyperglycemia and aggressive treatment in the young
especially with increasing body weight
Conclusion

20. Thank You
Endless story