Explain the diagnosis and symptoms of type I diabetic and outline how a lack of insulin

affects metabolism.

Insulin is synthesised in and secreted from the β cells of the pancreas.

The α cells of the pancreas produce glucagon.
The δ cells of the pancreas produce somatostatin.
The β cells are the most numerous and are mainly located in the core of the islet, whilst
α ∧δ cells are located in the periphery.

The insulin molecule consists of 2 polypeptide chains linked by disulfide bridges.

Insulin is formed in the islet β cellsfrom a single amino acid chain precursor molecule called
proinsulin. Synthesis begins with the formation of preproinsluin, which is cleaved by
protease activity to proinsluin. Proinsulin is packaged into vesicles in the golgi apparatus of
the cell, and in the maturing secretory granules it is converted into insulin and connecting
peptide (C peptide).
Insulin and C peptide are released via exocytosis from the β cell when the granules are
transported to the cell surface and the granule membrane fuses with the plasma membrane
of the β cell .

Glucose is the main stimulator of insulin release from the β cell, which occurs in a
characteristic biphasic pattern – an acute , first phase lasting only a few minutesm followed
by a sustained second phase.

The Glut 4 is the insulin sensitive glucose transporter. Glut 4 is normally loacted in the
cytoplasm. Insluin recruits the vesicles and causes them to be translocated to the cell
surface where GLUT-4 functions as a pore for glucose entry. Exercise has a similar effect on
GLUT-4.

Type I diabetes

Ketoacidosis
The acetyl coA formed in fatty acid oxidation enters the citric acid cycle only if fat and
carbohydrate degradation are appropriately balanced. Acetyl CoA must combine with
oxaloacetate to gain entry to the citric acid cycle. The availability of oxaloacetate, however,
depends on an adequate supply of carbohydrate. Oxaloacetate is normally formed from
pyruvate, the product of glocose degradation in glycolysis, by pyruvate carboxylase. If
carbohydate is unavailable or improperly utilized, the concentration of oxaloacetate is
lowered and acetyl coA cannot enter the citric acid cycle.
In fasting or diabetes, oxaloacetate is consumed to form glucose by the gluconeogenic
pathway and hence is unavailable for condensation with acetyl coA. Under these conditions,
acetyl coA is iverted to the formation of acetoacetate and D-3 hydroxybutyrate.
Acetoacetate, D-3 hydroxybutyrate and acetone are referred to as ketone bodies.

Diabetic ketosis results when insulin is absent

In the absence of insulin, fats are released from adipose tissue, and glucose cannot be
absorbed by the liver or adipose tissue. The liver degrades the fatty acids by β oxidation but
cannot process the acetyl coA, because of a lack of glucose derived oxaloacetate. Excess
ketone bodies are formed and released into the blood.

Diabetic ketoacidosis (DKA) is a complex disordered metabolic state characterized by

hyperglycemia, ketoacidosis, and ketonuria. DKA usually occurs as a consequence of
absolute or relative insulin deficiency that is accompanied by an increase in counter-
regulatory hormones (ie, glucagon, cortisol, growth hormone, epinephrine). This type of
hormonal imbalance enhances hepatic gluconeogenesis, glycogenolysis, and lipolysis.

Insulinopenia : inadequate insulin secretion

Normal inslun release

 Glucose in blood
 GLUT2 transporter brings glucose from blood into beta cell of pancreas. This is
closely associated with the enzyme glucokinase, which phosphorylates glucose and is
the essential glucose sensor of the beta cell.
 In order for insluin release to occur, glucose must be metabolized within the beta
cell, via glycolysis, to produce ATP. This closes ATP sensitive potassium channels,
causing depolarization, which then leads to an influx of calcium ions, triggering
granule translocation and exocytosis.
 Sulphonylureas also act in a similar way by vlosing potassium channels. But these are
not useful in treating type 1 diabetes.

Diabetes type I (autoimmune)

Type I diabetes arises due to autoimmune destruction of beta cells in the pancreas in 90% of
cases.
The classical symptoms of type I diabetes are :
 polyuria,
 polydipsia (excessive thirst),
 polyphagia (excessive eating)
 Unexplained weight loss
Other symptoms may include fatigue, nausea and blurred vision. The onset of symptomatic
disease may be sudden. It is not unusual for patients with type 1 diabetes to present with
diabetic ketoacidosis.

Signs: muscle wasting, dehydration, weight loss

Usually has a sudden or rapid onset. Usually picked up early in life.
C-peptide is absent
Very prone to ketosis.
Sensitive to insulin.
Diet modifications are insufficient with insulin. Sulphoylureas are ineffective in management
of Type I diabetes.

Diagnosis:
A fasting plasma glucose (FPG) level ≥ 7.0 mmol /L
A 2-hour plasma glucose level of 11.1 mmol/ L during a 75g oral glucose tolerance test
(OGTT)
A random plasma glucose (≥ 11.1mmol /L in a patient with classic symptoms of
hyperglycemia or hyperglycemic crisis.

Hemoglobin A
HbA1c is the stable product of nonenzymatic irreversible glycation of the beta chain of
hemoglobin by plasma glucose and is formed at rates that increase with increasing plasma
glucose levels. HbA1c levels provide an estimate of plasma glucose levels during the
preceding 1-3 months. The reference range for nondiabetic people is 6% in most
laboratories. Glycated hemoglobin levels also predict the progression of diabetic
microvascular complications. Advantages of HbA1C testing u=include
 Ability to capture long-term glucose exposure
 Less biologic variability
 No requirement for fasting or timed samples

Differentiation of Type 1 from Type 2 diabetes

C-peptide is formed during conversion of proinsulin to insulin. An insulin or C-peptide level
below 5 µU/mL (0.6 ng/mL) suggests type 1 DM.

The autoimmune destruction of pancreatic β-cells leads to a deficiency of insulin secretion.

It is this loss of insulin secretion that leads to the metabolic derangements associated with
IDDM.

Metabolism
In the absence of insulin replacement type 1 diabetes is a catabolic condition with severe
depletion of both energy stores and protein mass. 

Glucose metabolism
Glucose Metabolism: Uncontrolled IDDM leads to increased hepatic glucose output. First,
liver glycogen stores are mobilized then hepatic gluconeogenesis is used to produce glucose.
Insulin deficiency also impairs non-hepatic tissue utilization of glucose. In particular in
adipose tissue and skeletal muscle, insulin stimulates glucose uptake. This is accomplished
by insulin-mediated movement of glucose transporter proteins to the plasma membrane of
these tissues. Reduced glucose uptake by peripheral tissues in turn leads to a reduced rate
of glucose metabolism. In addition, the level of hepatic glucokinase is regulated by insulin.
Therefore, a reduced rate of glucose phosphorylation in hepatocytes leads to increased
delivery to the blood. Other enzymes involved in anabolic metabolism of glucose are
affected by insulin (primarily through covalent modifications). The combination of increased
hepatic glucose production and reduced peripheral tissues metabolism leads to elevated
plasma glucose levels. When the capacity of the kidneys to absorb glucose is
surpassed, glucosuria ensues. Glucose is an osmotic diuretic and an increase in renal loss of
glucose is accompanied by loss of water and electrolytes, termed polyuria. The result of the
loss of water (and overall volume) leads to the activation of the thirst mechanism
(polydipsia). The negative caloric balance which results from the glucosuria and tissue
catabolism leads to an increase in appetite and food intake (polyphagia).
Glucokinase is an enzyme that phosphorylates glucose. Phosphorylates glucose for making
glycogen for storage.

Lipid Metabolism
Normally, the levels of malonyl-CoA are high in the presence of insulin. These high levels of
malonyl-CoA inhibit carnitine palmitoyltransferase I, the enzyme required for the transport
of fatty acyl-CoA's into the mitochondria where they are subject to oxidation for energy
production. Thus, in the absence of insulin, malonyl-CoA levels fall and transport of fatty
acyl-CoA's into the mitochondria increases. Mitochondrial oxidation of fatty acids generates
acetyl-CoA which can be further oxidized in the TCA cycle. However, in hepatocytes the
majority of the acetyl-CoA is not oxidized by the TCA cycle but is metabolized into the
ketone bodies, acetoacetate and β-hydroxybutyrate. These ketone bodies leave the liver
and are used for energy production by the brain, heart and skeletal muscle. In IDDM, the
increased availability of free fatty acids and ketone bodies exacerbates the reduced
utilization of glucose furthering the ensuing hyperglycemia. Production of ketone bodies, in
excess of the organisms ability to utilize them leads to ketoacidosis. In diabetics, this can be
easily diagnosed by smelling the breath. A spontaneous breakdown product of acetoacetate
is acetone which is volatilized by the lungs producing a distinctive odor.
Normally, plasma triglycerides are acted upon by lipoprotein lipase (LPL), an enzyme on the
surface of the endothelial cells lining the vessels. In particular, LPL activity allows fatty acids
to be taken from circulating triglycerides for storage in adipocytes. The expression of LPL is
regulated by insulin and in its absence a hypertriglyceridemia results. Insulin is a potent
stimulator of LPL.

Malonyl coA is involved in the fatty acid synthesis pathway. So when glucose high, insulin
should rise and so you don’t need fats as a source of energy so you can store them (fatty
acid synthesis)

Protein metabolism
Insulin deficiency will lead to increased catabolism of protein. The increased rate of
proteolysis leads to elevated concentrations in plasma amino acids. These amino acids serve
as precursors for hepatic and renal gluconeogensis. In liver, the increased gluconeogenesis
further contributes to the hyperglycemia seen in IDDM.

Metabolic effects of insulin

tabolic Effects of INSULIN
A. on carbohydrate metabolism:
1. increases glucose transporters in cells and membranes (muscle, adipose tissue)
2. increases glycogen synthase activity (liver, muscle, adipose tissue)
3. increases glycolysis (liver, muscle, adipose via stimulation of energy requiring
 anabolic processes) 4. decreases glycogenolysis and gluconeogenesis (liver)
5. increases glucokinase activity (liver, enables liver to increase its uptake of glucose)
B. on lipid metabolism:
6. decreases lipolysis in adipose tissue
7. decreases ketone body synthesis in liver
8. increases fatty acid and triacylglycerol synthesis in liver and adipose tissue
C. on protein metabolism:
9. increases amino acid transport into muscle, adipose tissue and liver
10. increases rate of protein synthesis in muscle, adipose tissue, liver and other cells
11. decreases rate of protein degradation