Insulin synthesis

Normal Pancreatic Function

Exocrine pancreas aids
digestion
Bicarbonate
Lipase
Amylase
Proteases

Endocrine pancreas
(islets of Langerhans)
Beta cells secrete insulin
Alpha cells secrete
glucagon
Other hormones
 Insulin Stimulates Cellular Glucose Uptake

Adipocytes
Skeletal Muscle
Liver

Insulin
Insulin Insulin

Intestine & Pancreas

Comparison between type 1 & type 2
DM
 Classification of diabetes
Type 1 diabetes (results from b-cell destruction,
usually leading to absolute insulin deficiency)

Type 2 diabets (progessive insulin secretory

defect on the background of insulin resistance)

Other types of diabets: genetic defects in b-cell

function; genetic defects in insulin action,
pancreatic diseases, drug/chemical induced

Gestational diabetes mellitus (GDM)- diabetes

diagnosed during pregnancy
 Criteria for the diagnosis of diabetes
HbA1c 6.5%
Or
Fasting plasma glucose 126mg/dl (fasting =
no caloric intake for at least 8h)
Or
2-h plasma glucose 200 mg/dlduting an
OGTT (WHO loading glucose 75 g dissolved
in water)
Or
Patient with classic symptoms of hyperglycemia
or hyperglycemic crisis, a random glucose
200 mg/dl
 Prediabetes categories of increased risk
for diabetes

Fasting plasma glucose 100- 125mg/dl

(=impaired fasting glucose)
Or
2-h plasma glucose in 75g OGTT 140-199
mg/dl
Or
Hba1c 5.7-6.4%
 Screening for and diagnosis of GDM
Screen for undiagnosed type 2 diabetes at the first
prenatal visit in those with risk factors using standard
diagnostic criteria if any criteria is positive- DM not
GDM!
In pregnant women - 24-28 weeks of gestation perform
OGTT GDM if:
- Fasting 92 mg/dl
- 1h 180 mg/dl
- 2h 153 mg/dl

Women with history of GDM should have lifelong screening

for the development of DM or prediabetes at least 3
years
 Markers for monitoring DM
Fasting glucose (N: 65 99 mg/dl)
OTTG 2h < 140 mg/dl
Hba1c < 5.7%
Insulin, CPE
CT, LDL-C, HDL-C, TG
Ketone bodies
Microalbuminuria < 20mg/dl
Ab anti insulin, B-cell of pancreatic islets, GAD
(Glutamic Acid Decarboxylase Autoantibodies)
 Type 1 Diabetes:
Hallmarks
Progressive destruction of beta cells

Decreased or no endogenous insulin

secretion

Dependence on exogenous insulin for

life
 Absence of Insulin

Glucose cannot be utilized by cells

Glucose concentration in the blood rises

Blood glucose concentrations can exceed renal

threshold

Glucose is excreted in urine

Onset of type 1 DM
 Presenting Symptoms of Type 1 Diabetes

Polyuria: Glucose excretion in urine

increases urine volume

Polydipsia: Excessive urination leads to

increased thirst

Hyperphagia: Cellular starvation

increases appetite
 Type 1 Diabetes Mellitus:
Background
Affects ~1 million people

Juvenile onset

Genetic component

Autoimmune/environmental etiology
 Normal
Insulin

Glycerol
Lipolysis

Free fatty acids

Triglyceride
Synthesis
Free fatty acids

LPL Glucose

Insulin
 Type 1 Diabetes Mellitus

Glycerol Lipolysis

Free fatty acids

Triglyceride
Synthesis

Free fatty acids

LPL Glucose
 Clinical Chemistry

Normal Uncontrolled Type 1

Fasting blood glucose < Fasting blood glucose up
100 mg/dL to 500 mg/dL

Serum free fatty acids Serum free fatty acids

~ 0.30 mM up to 2 mM

Serum triglyceride ~100 Serum triglyceride

mg/dL > 1000 mg/dL
Insulin Regulation of Hepatic Fatty Acid
Partitioning

FA-CoA

TG ATP, CO2 -hydroxybutyrate

acetoacetate

Mitochondrion
 In Liver:
FFA Entry into Mitochondria is Regulated by
Insulin/Glucacon

Malonyl CoA

carnitine carnitine

FA-CoA CPT-I CPT-II FA-CoA

ATP, CO2 HB, AcAc

outer inner
TG Mitochondrial
membranes
CPT= Carnitine Palmitoyl
Transferase
Malonyl CoA is a Regulatory Molecule

Condensation of CO2 with acetyl CoA forms

malonyl CoA

First step in fatty acid synthesis

Catalyzed by acetyl CoA carboxylase

Enzyme activity increased by insulin

 Ketone Bodies
Hydroxybutyrate, acetoacetate
Fuel for brain
Excreted in urine

At 12-14 mM reduce pH of blood

Can cause coma (diabetic ketoacidosis)
 Natural History Of PreType 1
Diabetes
Putative
trigger
-Cell Cellular autoimmunity
mass 100%
Circulating autoantibodies (ICA, GAD65)

Loss of first-phase
insulin response (IVGTT)
Clinical
Glucose intolerance onset
(OGTT) only
10% of
-cells
remain
Genetic Insulitis Pre-
predisposition -Cell injury diabetes Diabetes

Time

Eisenbarth GS. N Engl J Med. 1986;314:1360-1368 14

Case 1
R.T., a 15-year-old male with type 1 diabetes
presented with a 5-day history of nausea and
vomiting. He also reported a 2-week history of
polyuria and polydipsia and a 10-lb weight loss.

The patient was diagnosed with type 1 diabetes 2

years ago when he presented to a different hospital
with symptoms of polyuria, polydipsia, and weight
loss.
The laboratory data showed an anion gap,
metabolic acidosis, and hyperglycemia (pH of 7.14,
anion gap of 24, bicarbonate 6 mmol/l, urinary
ketones 150 mg/dl, glucose 314 mg/dl) consistent
with the diagnosis of DKA. The patient's hemoglobin
A1c (A1C) was 13.5%.
 The Miracle of Insulin

Patient J.L., December 15, February 15, 1923

1922
 Metabolic changes of type 1 DM (cont.)
Metabolic & Clinical Abnormalities in DKA
Low Insulin

Carbohydrates Lipids Metabolism

Protein
Metabolism Metabolism
Lipolysis
in Adipose Tissue
Proteolysis
Uptake of AA
In Sk. Ms. & Adipose In
In
by liver
Fatty Acids
Liver
Glucose Uptake in liver
Hyperglycemia
Glycogenlysis
Plasma
Osmolality
Gluconeogenesis
Gluconeogenesis Coma
ketone Bodies Prerenal Uremia
Gluconeogenesis
Glycosuria (KETOGENESIS)

Metaboli Low
Osmotic diuresis Ketonemi c Renal H+
With Loss of water & Na+ a Acidosis Excretion
Low
& Hypovolemia Nausea Acetone Increased Blood
& Ketonuria Smelt Respiration Bicarbona
on Breath te
Polyuria, Vomiting
Thirst &
Low pCO2
Dehydration Low GFR
 Primary Defect in Type 2

Study healthy 1st degree relatives of

patients with type 2

Measure ability of body to use glucose

Find defects in muscle glucose uptake

before any symptoms develop
 Why is Glucose Transport Reduced?

Mitochondrial phosphorylation decreased 30%

Intramyocellular lipid is increased 80%

Ectopic fat may hinder insulin-stimulation of

glucose transport.
 What is consequence of muscle
insulin resistance?

Pancreas compensates >

hyperinsulinemia

Hyperinsulinemia exacerbates insulin

resistance in adipose tissue.
Consequences of Insulin Resistance in
Adipose Tissue

Similar to insulin deficiency

Reduced TG synthesis

Enhanced lipolysis

Net increase in FA availability to non-adipose

tissues
 Consequences of Insulin Resistance
FFA in Muscle
Increased intramyocellular lipid

Hypothetical: inhibition of insulin

signaling by diglyceride

Reduction in glucose uptake by muscle

 Consequences of Insulin Resistance
FFA in Liver
Increased triglyceride synthesis

Increased oxidation

Increased gluconeogenesis

Hepatic glucose output contributes to

hyperglycemia
 Consequences of Insulin Resistance
FFA in Pancreas

Animal models of diabetes

Lipid droplets accumulate in beta cells

Beta cells undergo apoptosis

Reduced beta cell mass

Decreased circulating insulin

KEY POINTS
Resistance to the actions of insulin is strongly associated with the
microvascular complications of diabetes, independently of metabolic
control and hypertension
Insulin resistance is an important marker of risk and a key target for
intervention, as those patients who achieve a greater improvement of
insulin sensitivity achieve better microvascular outcomes
Diabetes and obesity are associated with pathway-selective insulin
resistance in the phosphatidylinositol-3-kinase signaling pathway,
while signaling via extracellular signal-regulated kinase dependent
pathways is comparatively unaffected, tipping the balance of insulins
actions in favor of abnormal vasoreactivity, angiogenesis, and other
pathways implicated in microangiopathy
Insulin resistance is able to enhance key pathways involved in
hyperglycemia-induced microvascular damage and to exacerbate
hypertension
The strong association between insulin resistance and microvascular
disease might also reflect a common genotype or phenotype