DM pathophysiology

1. Diabetes Mellitus –
Pathophysiology
Dr. Choure Balwant
Associate Professor
Department of Pharmacology
DVVPF’s Medical college Ahmednagar

2. 1. Basic information about pancreas & β cells
2. How insulin is secreted…
3. Mechanism of insulin action ….
4. Natural history of Type 2 DM…
5. Endocrine abnormalities in Type 2 DM….

3. • There are about 1 million islets.
• Equals 2% of the volume of pancreas.
• Each Islet Contains 2,000 beta Cells
• Total beta cells = 200 Crore
• Beta Cells are capable of sensing changes in
Blood Glucose as low as 2 mgs % within seconds.
• Can store as much as 200 units of Insulin
Pancreas and Islets of Langerhans

4. •  cells – produce glucagon. is catabolic, mobilizing
glucose, fatty acids & amino acids from stores into the
blood stream; tends to ↑ BSL by stimulating hepatic
glycogenolysis and glucogenesis; ↑es lipolysis in adipose
tissue
•  cells – produce insulin & amylin. Insulin is anabolic, ↑ng
the storage form of glucose , fatty acids & amino acids
• δ cells – produce somatostatin & gastrin, which inhibits
secretion of insulin, glucagon and pancreatic polypeptide
• F (PP) cells – production of pancreatic polypeptide, which
slows absorption of food.
• Epsilon cells -- secrete a hormone called ghrelin.
Major cell types in the islets of Langerhans

5. • “Counterregulatory” hormones oppose the
actions of insulin & promote glucose release…...
(1) Glucagon (2) Catecholamine (E & NE)
(3) Glucocorticoid- cortisol (4) Growth hormone
• Glucagon-like peptide-1 (GLP-1) from the GI tract
enhances insulin release in response to an
ingested meal.
• Amylin suppresses endogenous production of
glucose in the liver.

7. • Basal Insulin secretion : 1.3 ± 0.4 unit / hr
• 24 hr total Insulin secretion : 63 ± 15 unit
• Basal Insulin secretion : 50 ± 8 % of total Insulin secretion
Insulin secretion rate in normal human on
standard Carb diet

8. • 51-amino acid protein composed of two peptide
chains that are linked by two disulfide bridges.
• Insulin is synthesized in the rough endoplasmic
reticulum of  cells
• Insulin is synthesized as a part of a larger molecule
pre pro insulin  proinsulin
• Proinsulin breaks to Insulin and C-peptide
• Insulin is rapidly degraded in the liver & kidney,
with a circulating half-life of 6 minutes.
Biosynthesis of Insulin

9. Pro insulin, Insulin and Connecting Peptide
Pro Insulin
Carboxy Peptidase
Insulin and C-Peptide
Pro Insulin 1 %, 10%-20% Insulin like, C V Risk Factor

10. Mechanism of Secretion of Insulin
VIDEO

11. • Insulin Binds to receptor - a tyrosine kinase R.
• Receptor has  subunit [extra cellular] &  subunit [trans
membrane]
• Binding of insulin to the  subunit cause  subunit to
phosphorylate [autophosphorylation] tyrosine residues
• It transfers phosphate groups from ATP to tyrosine
residues on intracellular target proteins
• The activated receptor then phosphorylates a number of
intracellular proteins and alters their activity
Mechanism of Action of Insulin

12. Insulin Receptor Signaling

13. Effects of Insulin
Principles of Pharmacology:
The Pathophysiologic Basis of Drug
Therapy by by David E. Golan

14. Reduces rate of release of glucose from liver by:-
1. Inhibiting glycogenolysis
2. Stimulating glycogen synthesis
3. Stimulating glucose uptake by GLUT 4 up-
regulation
4. Stimulating glycolysis
5. Inhibiting gluconeogensis
↑es rate of uptake of Glucose into all insulin
sensitive tissues  muscle & adipose tissue
On Carbohydrate Metabolism..

15. • Glucose enters cells with the help of transporters,
GLUT 1 to GLUT 6
• GLUT 1 in Brain, GLUT 3 Brain / Kidney
• GLUT 2 in Beta cells & Liver
• GLUT 5 for Fructose Jejunum, Liver , Sperm
• GLUT 4 is the glucose transporter in muscle & adipose
tissue which is stimulated by insulin.
• GLUT 4 needs Insulin : IMGU Insulin Mediated Glucose Uptake
• Other GLUTS : NIMGU Non Insulin Mediated Glucose Uptake
GLUT : for Glucose uptake

16. • Reduces rate of release of FFA from adipose tissue
• Stimulates de novo synthesis of FFA & also
conversion of FA to triglycerides in liver.
On Lipid Metabolism..
Insulin : Lipogenic Hormone

17. • Stimulates transport of free amino acids across
the plasma membrane in liver & muscle
• Stimulates protein synthesis & reduces release
of amino acids from muscle
On Protein Metabolism..
Insulin : Anabolic Hormone

19. What is diabetes?
DM is a group of diseases characterized by high
levels of blood glucose resulting from defects in
insulin production, insulin action, or both.
a metabolic disorder of multiple aetiology
characterized by chronic hyperglycaemia with
disturbances of carbohydrate, fat & protein
metabolism
The effects of DM include long–term damage,
dysfunction and failure of various organs.

20. Diabetes
characteristic symptoms such as Thirst, Polyuria,
Blurring Of Vision & Weight Loss.
In its most severe forms, ketoacidosis or a non–
ketotic hyperosmolar state may develop & lead
to stupor, coma and in absence of effective
treatment death.
Often symptoms are not severe or may be
absent & consequently hyperglycaemia sufficient
to cause pathological & functional changes may
be present for a long time before the diagnosis is
made.

21. Diabetes Long-term Effects
1. Retinopathy with potential blindness
2. Nephropathy that may lead to renal failure,
and/or
3. Neuropathy with risk of foot ulcers, amputation,
Charcot joints and
4. Features of autonomic dysfunction -- sexual
dysfunction.
5. increased risk of cardiovascular, peripheral
vascular & cerebrovascular disease.

22. Types of DM
1. Type 1 DM
2.Type 2 DM
3. Gestational Diabetes (GDM)
4. Other types:
 LADA (Latent Autoimmune Diabetes in Adults)
(mistakenly thought to have type 2 DM)
 MODY (Maturity-onset Diabetes of Youth)
 Secondary DM

23. Type 1 DM
previously k/a insulin-dependent DM (IDDM) / or
juvenile-onset diabetes.
body’s immune system destroys pancreatic β
cells that make the hormone insulin that
regulates BSL.
usually strikes children & young adults, although
disease onset can occur at any age.
 5 -10% of all diagnosed cases of DM.
Risk factors for type 1 DM  Autoimmune,
genetic & environmental factors.

24. Type 2 DM
previously k/a non-insulin-dependent DM
(NIDDM) / or adult-onset diabetes.
90-95% of all diagnosed cases of DM.
begins as insulin resistance, a disorder in which
the cells do not use insulin properly.
As the need for insulin rises, the pancreas
gradually loses its ability to produce insulin.

25. is a/w older age, obesity, family h/o DM, h/o
GDM, impaired glucose metabolism, physical
inactivity & race/ethnicity.
African Americans, Hispanic/Latino Americans,
American Indians, and some Asian Americans and
Native Hawaiians or Other Pacific Islanders are at
particularly high risk for type 2 DM.
Type 2 DM is increasingly being diagnosed in
children and adolescents.
Type 2 DM

27. Drug induced hyperglycemia
increased insulin
resistance
Corticosteroids
Atypical Antipsychotics
Naicin
Inhibit insulin
secretion.
Beta-blockers Calcium Channel
Blockers
Fluoroquinolones
Phenothiazines
Thiazide Diuretics
Inhibit the conversion
of proinsulin to insulin.
Protease Inhibitors

28. Prediabetes: Impaired glucose tolerance &
impaired fasting glucose
 Prediabetes - a term used to distinguish people who are
at increased risk of developing DM.
 People with prediabetes have impaired fasting glucose
(IFG) / impaired glucose tolerance (IGT) OR both.
 IFG = the fasting BSL is elevated (100 to 125 mg/dL) after
an overnight fast but is not high enough to be classified
as DM.
 IGT = the BSL is elevated (140 to 199 mg/dL after a 2 hr
OGTT), but is not high enough to be classified as DM.

29. Prediabetes: IGT & IFG (cont.)
• Progression to DM among those with prediabetes
is not inevitable.
• Studies suggest that weight loss & ↑ed physical
activity among people with prediabetes prevent /
delay DM & may return BSL to normal.
• People with prediabetes are already at ↑ed risk
for other adverse health outcomes such as heart
disease & stroke.

30. Type 2 Diabetes Mellitus

31. • Diabetes does not develop overnight
• There is relative contribution by Insulin deficiency &
Insulin resistance both
• Pathophysiolgy is not static, it is dynamic
• Therapy should match pathophysiology
• Chronic Hyperglycemia is a/w microvascular,
macrovascular & metabolic complications

32. Insulin
Resistance
Glucagon
Hypersecretion
Insulin
Deficiency
Hyperglycemia
GI Hormones
GLP 1
Amylin
GIP
T2 DM - Multihormonal Hypothesis

33. • In normal subjects insulin sensitivity & insulin secretion are
related to each other in a hyperbolic manner
Relationship of Insulin Secretion & Insulin
Action in Type 2 DM
• Disposition Index [DI] = Insulin sensitivity x Insulin secretion
Insulin sensititivity

34. • In healthy individuals, reductions in insulin sensitivity
(↑ed IR)  adaptations of insulin secretion from the β-
cell, resulting in normal glucose processing.
• However, if this adaptive mechanism fails & loss of β-cell
function becomes progressive reduced insulin
secretion, IGT & T2DM.
AbN pancreatic islet function determines the
development of IGT and T2DM in the setting of Insulin
Resistance (IR)
Relationship of Insulin Secretion & Insulin Action in Type 2 DM

35. Age, Lifestyle,
Environmental Factors
Insulin Resistance
Normal Islet
Function
NGT IGT / T2DM
Abnormal
Islet Function
Beta cell Dysfunction MUST for T2DM

36. • Muscles--- ↓ed ability of muscle to store / oxidize
glucose in patients with IGT  release of lactate into the
circulation
• Adipose tissue -- inadequate insulin action  ↑ed
release of glycerol & FFA.
• FFA provide energy for gluconeogenesis & lactate &
glycerol are gluconeogenic substrates.

37. • Furthermore, impaired α-cell function  excessive
glucagon release during fasting & PP states 
development & progression of hyperglycemia.
• Thus, IR in the context of progressive islet dysfunction
 increasingly excessive fasting & PP hepatic glucose
production hyperglycemia.
• Thus the diagnosis of T2DM often occurs well beyond
the initial decline in pancreatic islet function.

38. Natural History of Type 2 Diabetes

39. Defective insulin sensitivity requires
hyperinsulinemia for preservation of
normoglycemia
this failure results in Type 2 DM
Nearly 6 % reduction in beta cell mass after T2 DM

40. Direct imaging : unsuccessful
Indirect tests :
Steady State :
Homeostatic model assessment (HOMA) is a method for
assessing β-cell function and insulin resistance (IR) from
basal (fasting) glucose & insulin/or C-peptide conc.
Non-Steady State :
• Beta cell Function : Hyperglycaemic clamp, IV GTT, OGTT
• C Peptide
Measuring beta-cell mass /function

41. Steady State :
Homeostatic Model Assessment- HOMA -IR
Non-Steady State :
• Insulin Resistance : Euglycemic clamp study
Measuring Insulin Resistance

42. HOMA estimates IR in the fasting state.
Surrogate marker for IR
Steady state IR : HOMA
fasting serum insulin (µU/ml) x FPG mg/dl)
405
HOMA IR : =
Using mass units :
fasting serum insulin (µU/ml) x FPG (mmol/l)
22.5
HOMA IR : =
Using molar units :

43. HOMA-IR CALCULATOR
Available from: http://www.thebloodcode.com/homa-ir-calculator/
Fasting Insulin (µIU/ml) 24
Fasting Glucose (mg/dL) 89
HOMA-IR 5.3
IR
< 1.7 : NO insulin resistance
> 1.7 : YES Insulin Resistance
HOMA : Interpretation

44. • Fasting Plasma glucose in mmol/l or mg/dl
• Fasting Insulin value in pmol/l or µU/ml
• Press ‘Calculate’
HOMA 2 Calculator

45. Diabetes is more than insulin deficiency
or resistance
•Other endocrine abnormalities in Diabetes :
1. GLP 1 (Glucagon Like Peptides) deficiency (Incretin Deficiency)
2. Glucagon secretion abnormality
3. Amylin deficiency

46. Insulin response
Oral glucose load
IV glucose infusion
•Insulin response is greater following oral glucose than IV
glucose, despite similar plasma glucose conc. due to
incretins
Plasma
glucose
(mmol/L)
–10 –5 60 120 180
10
Time (min)
5
0
15
Plasma glucose
90
0
180
270
Plasma
glucose
(mg/dL)
* *
*
*
* * *
IR-insulin
(mU/L)
80
60
40
20
–10 –5 60 120 180
0
Time (min)
Incretin
effect
Nauck et al. Diabetologia 1986;29:46–52
Incretin Effect

47. • Some hormone from intestine having endocrine
effect on pancreas : Incretin Effect : Intestine
mediated secretion of Insulin
• G protein-mediated pathways, parasympathetic
activity & GI hormones GLP-1 & glucose-
dependent insulinotropic polypeptide (GIP) also
inhibit K /ATP channel activity & stimulate insulin
secretion.
Incretins

48. L-cell
(ileum)
Proglucagon
GLP-1 [7–37]
GLP-1 [7–36 NH2]
K-cell
(jejunum)
ProGIP
GIP [1–42]
GLP-1 & GIP are Synthesized & Secreted from the Gut in
Response to nutrient intake: primarily glucose & fat.

49. GLP-1
suppresses glucagon secretion.
delays gastric emptying
at the hypothalamus to decrease appetite.
• short half life = 1–2 minutes due to enzymatic
degradation by dipeptidyl peptidase-4 (DPP-4) .

50. Glucagon
• a single-chain polypeptide o 29 amino acids.
• Besides low glucose & high insulin levels - stimuli
for glucagon secretion include sympathetic
nervous system activity, stress, exercise & high
plasma levels of amino acids (because the latter indicates a
state of starvation).
• Glucagon promotes 1.Hepatic Glycogenolysis
2. Gluconeogenesis 3.Lipolysis in adipose tissue.
• The liver & kidneys degrade glucagon; like insulin,
its circulating half -life is about 6 minutes.

51. Fasting
Postprandial
Appropriate and timely secretion of insulin and glucagon
is of utmost importance
Normal Pattern of Glucagon & Insulin
Secretion

52. Insulin and glucagon secretion in normal subjects &
Type 2 DM

53. What incretin GLP-1 does in T2 DM

54. Amylin
• 37-amino acid protein that is packaged together
with insulin in secretory granules
• Insulin & amylin are co-secreted following a
meal. Amylin binds receptors within the CNS & its
glucoseregulatory actions complement those of
insulin.
• Amylin suppresses glucagon release.. slows
gastric emptying….& decreases food intake. 
gradual entry of glucose into the circulation
following a meal.
• Amylin is cleared by the kidney; its half -life is
• approximately 10 minutes.

55. Somatostatin
• 14 & 28-amino acid forms --pancreatic δ cells, GIT
& hypothalamus.
• inhibits………
(1) release of pituitary GH & TSH
(2) secretion of insulin & glucagon
(3) GI motility & the release of various GI hormones.
• The stimuli its release are similar to those for
insulin (i.e., high plasma levels of glucose, amino acids & atty acids).
• The circulating half life = only 2 minutes.

56. Hepatic Glucose Output (HGO)
&
High Glucagon

57. Glucose Entry
Meal related glucose
Endogenous: Glycogenolysis (Liver), Gluconeogenesis (Liver & Kidney)
Glucose Disposal
NIMGU : Brain, liver etc , IMGU : Muscle, adipose tissue
Plasma glucose will ↑ if rate of entry exceeds
rate of exit

58. Hepatic Glucose Production is Elevated in
Type 2 DM
Adapted with permission from Pehling G et al. J Clin Invest. 1984;74:985–991.
Mixed Meal
Fasting Fed
Glucose uptake
Meal derived glucose
Hepatic glucose production
Hepatic glucose production
Glucose uptake
Meal derived glucose
Diabetic Subjects
Nondiabetic Controls
Glucose
Flux
(mg·kg
-1
·min
-1
)
Glucose
Flux
(mg·kg
-1
·min
-1
)
Fasting Fed

59. • HGO : [2mg/kg/min, 85 % from HGO and 15% from Renal ]
• Insulin production :Basal [1U/hr] and for meals [ based on meal ]
• Fasting state : 25 % IMGU, 75 % NIMGU
• NIMGU is fixed, IMGU is variable
• If HGO is increased & IMGU does not increase :
hyperglycemia
Hepatic Glucose Output (HGO)
&
hyperglycemia

60. Β cell as well as α cell dysfunction with IR leads to
all consequences
1. Reduced entry of glucose into peripheral tissues
2. Increased release of glucose from liver
3. Predisposition to CV disease as a result of IR at
vascular tissue, lipid metabolism etc.
The Fundamental Facts in T2 DM

61. Atherosclerosis as a consequence of IR
Insulin Resistance
Effects on VSMC (vascular smooth muscle cell)
Effects on Growth Factors
Effects on Sodium Absorption
Effects on PAI-1 (Plasminogen activator inhibitor-1)

62. DM & Atherosclerosis
Insulin Resistance
Increased CVD even if Normoglycemia
Beta cell exhaustion & Hyperglycemia
Exacerbation of vasculopathy by Hyperglycemia

63. CAD in T2 DM -- “Diabetics have presence of
underlying vascular disease even at diagnosis”
Diabetics without MI in past = Non Diabetics with MI in past

64. • Clock for macroangiopathy starts ticking many years
prior to onset of Diabetes (Brain /Heart/ PVD)
• Clock for microangiopathy starts ticking with
hyperglycemia ( Eye / Kidney/ Peripheral Neuropathy)
Ticking Clock Hypothesis

65. Diagnosis of Diabetes Mellitus

66. • Fasting = no caloric intake for at least 8 hrs.
• The 2-hr PP glucose test should be
performed using a glucose load containing
the equivalent of 75g anhydrous glucose
dissolved in water.
International Diabetes Federation
(IDF) Diabetes Atlas 9th edition 2019

67. Diabetes diagnostic criteria
Condition
2 hr* plasma
glucose
Fasting plasma
glucose
HbA1c
mmol/l (mg/dl) mmol/l (mg/dl) %
Normal < 7.8 (< 140) < 6.1 (< 110) < 6.0
Impaired Fasting
Glucose
< 7.8 (< 140)
≥ 6.1 (≥ 110) &
< 7.0 (<126)
6.0 - 6.4
Impaired Glucose
Tolerance
≥ 7.8 (≥ 140) < 7.0 (<126) 6.0 - 6.4
DM ≥ 11.1 (≥ 200) ≥ 7.0 (≥126) ≥ 6.5
National Health Portal
The Ministry of Health and Family Welfare
Government of India 2018

68. ICMR Guidelines 2018
Diagnostic Criteria for DM
 Symptoms of DM - Polyuria, Polydipsia, Weight loss in spite of
polyphagia, Tiredness, Weakness, Generalized pruritus, Recurrent
urogenital inf. Delayed wound healing plus
Casual or Random plasma glucose ≥ 200 mg/dl ( without regard
to time of last meal)
Fasting plasma glucose ≥ 126 mg/dl*
2 hr post 75 g glucose ≥ 200 mg/dl (as part of OGTT)*
Glycated Haemoglobin ≥ 6.5%*
*DM diagnosed using any of these criteria should be
confirmed with another test subsequently.

69. Ref- ICMR Guidelines 2018

70. Aim of Management of T2 DM
 Prevention / Delay
 To achieve Normoglycemia
 To prevent CV disease

71. Prevention or delay of DM:
Life style modification
 Research studies have found it can prevent / delay the
onset of type 2 DM among high-risk adults.
 These studies included people with IGT and other high-
risk characteristics for developing DM.
 Lifestyle interventions included diet & moderate-
intensity physical activity (e.g. walking for 2.5 hrs each week).
 In the DM Prevention Program, a large prevention
study of people at high risk for DM, the development
of DM was reduced 58% over 3 years.

72. Prevention or delay of DM :
Medications
 successful in preventing DM
 In the Diabetes Prevention Program, people treated with
the drug Metformin reduced their risk of developing DM
by 31% over 3 years.
 Treatment with Metformin was most effective among
younger, heavier people (those 25-40 years of age who were 50 to 80
pounds overweight) & less effective among older people &
people who were not as overweight.

73.  Similarly, in the STOP-NIDDM Trial, treatment of
people with IGT with the drug Acarbose reduced the
risk of developing DM by 25% over 3 years.
 both lifestyle changes and medication have also been
shown to increase the probability of reverting from
IGT to normal glucose tolerance.

74. Strategy : Glycemic Control T2 DM
• Early Stage : Preserve beta cell functions
• Intermediate : Enhance beta cell function
• Late Stage : Replace beta cell function
Most of T2 DM will need Insulin Replacement

75. Management of DM
• The major components of the treatment of DM are:
• Diet and Exercise
A
• Oral hypoglycaemic
therapy
B
• Insulin Therapy
C

76. A. Diet
 Diet is a basic part of management in every case.
Treatment cannot be effective unless adequate
attention is given to ensuring appropriate nutrition.
Dietary treatment should aim at:
1. Ensuring weight control
2. Providing nutritional requirements
3. Allowing good glycaemic control with blood glucose
levels as close to normal as possible
4. Correcting any associated blood lipid abnormalities

77. A. Diet (cont.)
Dietary guidelines for people with DM:
 Dietary Fat should provide 25-35% of total intake of
calories but saturated fat intake should not exceed 10% of
total energy.
 Cholesterol consumption should be restricted and limited to 300
mg or less daily.
 Protein intake can range between 10-15% total energy
(0.8-1 g/kg of desirable body weight).
 Requirements increase for children and during pregnancy.
 Protein should be derived from both animal & vegetable
sources.

78.  Carbohydrates provide 50-60% of total caloric content
of the diet.
 Carbohydrates should be complex and high infibre.
 Excessive salt intake is to be avoided.
 It should be particularly restricted in people with
hypertension and those with nephropathy.

79. Exercise
 Physical activity promotes weight reduction & improves
insulin sensitivity, thus lowering blood glucose levels.
 Together with dietary treatment, a programme of regular
physical activity and exercise should be considered for
each person. Such a programme must be tailored to the
individual’s health status and fitness.
 People should, however, be educated about the
potential risk of hypoglycaemia and how to avoid it.

80. Self-Care
Patients should be educated to practice self-care.
This allows the patient to assume responsibility &
control of his / her own diabetes management.
Self-care should include:
1. Blood glucose monitoring
2. Body weight monitoring
3. Foot-care
4. Personal hygiene
5. Healthy lifestyle/diet or physical activity
6. Identify targets for control
7. Stopping smoking

81. References
• National Diabetes Fact Sheet 2003, DEPARTMENT OF HEALTH AND HUMAN
SERVICES Centres for Disease Control and Prevention
• World Health Organization. Definition, Diagnosis and Classification of Diabetes
Mellitus and its Complications. Report of WHO. Department of Non-communicable
Disease Surveillance. Geneva 1999
• Academy of Medicine. Clinical Practice Guidelines. Management of type 2 diabetes
mellitus. MOH/P/PAK/87.04(GU), 2004
• NHS. Diabetes - insulin initiation - University Hospitals of Leicester NHS Trust
Working in partnership with PCTs across Leicestershire and Rutland, May 2008.
• Ahrén B, Pacini G. Islet adaptation to insulin resistance: mechanisms and implications
for intervention. Diabetes Obes Metab. 2005; 7: 2–8.
• Dunning BE, et al. Alpha cell function in health and disease: influence of glucagon-like
peptide-1. Diabetologia. 2005; 48: 1700–1713.
•