Case 7 - diabetes management
1. What is the difference between type 1 and type 2 diabetes?
Causes T2DM
Mostly a family history of type 2 diabetes, but also obesity, sedentary lifestyle, increasing age and a bad diet
Prevalence
The global prevalence of diabetes* among adults over 18 years of age rose from 4.7% in 1980 to 8.5% in 2014
(WHO). The number of people with diabetes rose from 108 million in 1980 to 422 million in 2014.
Approximately 90-95% has diabetes type 2. The majority living in low-and middle-income countries, and 1.6
million deaths are directly attributed to diabetes each year.
Symptoms T2DM
- peeing more than usual, particularly at night
- feeling thirsty all the time
, - feeling very tired
- losing weight without trying to (because protein and fat utilized as alternative energy source to
glucose)
- itching around your penis or vagina, or repeatedly getting thrush
- cuts or wounds taking longer to heal
- blurred vision (alters shape of the lens)
- Increased urine output (when glucose levels exceed threshold 9-10 mmol/l the kidney eliminates
glucose through increased urine production = excessive water loss.
Diagnosis
- Glycated hemoglobin (A1C) test. Most commonly used! This blood test indicates your average
blood sugar level for the past two to three months. Normal levels are below 5.7 percent, and a
result between 5.7 and 6.4 percent is considered prediabetes. An A1C level of 6.5 percent or
higher on two separate tests means you have diabetes.
- Random blood sugar test. Blood sugar values are expressed in milligrams per deciliter (mg/dL) or
millimoles per liter (mmol/L). Regardless of when you last ate, a blood sample showing that your
blood sugar level is 200 mg/dL (11.1 mmol/L) or higher suggests diabetes, especially if you also
have signs and symptoms of diabetes, such as frequent urination and extreme thirst.
- Fasting blood sugar test. A blood sample is taken after an overnight fast. A reading of less than
100 mg/dL (5.6 mmol/L) is normal. A level from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) is
considered prediabetes. If your fasting blood sugar is 126 mg/dL (7 mmol/L) or higher on two
separate tests, you have diabetes.
- Oral glucose tolerance test. This test is less commonly used than the others, except during
pregnancy. You'll need to fast overnight and then drink a sugary liquid at the doctor's office.
Blood sugar levels are tested periodically for the next two hours. For this test, you fast overnight,
and the fasting blood sugar level is measured. Then you drink a sugary liquid, and blood sugar
levels are tested periodically for the next two hours. A blood sugar level less than 140 mg/dL (7.8
mmol/L) is normal. A reading between 140 and 199 mg/dL (7.8 mmol/L and 11.0 mmol/L)
indicates prediabetes. A reading of more than 200 mg/dL (11.1 mmol/L) after two hours indicates
diabetes.
2. How does insulin regulation work in healthy individuals?
Insulin production and secretion in liver
The islets of Langerhans are scattered throughout the pancreas, these are endocrine cells and make
up 2% of the total liver mass. The islets of Langerhans consist of:
, - B-cells: nearly three-quarter of the islet cells, produce insulin and amylin.
- Alpha-cells: 20% of islets cells, secrete glucagon
- PP cells: rare cells which produce pancreatic polypeptide
Insulin is synthesized as an inactive prohormone and is activated prior to secretion.Before secretion the
proinsulin is cleaved into insulin and C-peptide. There are several factors which can trigger secretion:
- Increased plasma glucose: glucose plasma concentrations greater than 100 mg/dL is a major stimulus.
Glucose absorbed from the small intestine reaches the pancreatic B-cells where it is taken up by
GLUT2 transporters. With more glucose available as substrate ATP production increases and ATP-
gated K+ channels close. The cell depolarizes, voltage gated Ca2+ channels open and Ca2+ entry
initiates exocytosis of insulin.
- Increased plasma amino acids
- Feedforward effect of GI hormones: 50% of insulin secretion is stimulated by GLP-1 and GIP, these
are incretin hormones produced by cells of the ileum and jejunum in response to nutrient absorption.
The incretins travel through the circulation to the B-cells and may reach them even before glucose is
absorbed. The anticipatory release of insulin prevents a sudden surge in plasma glucose
concentrations when the meal is absorbed.
- Nervous system
- Parasympathetic activity: increases during and following a meal and stimulates insulin
secretion
- Sympathetic activity: insulin secretion is inhibited by sympathetic neurons, (nor)epinephrine
inhibits insulin secretion and switches metabolism to gluconeogenesis to provide extra fuel
for the nervous system and muscles.
, Insulin receptor mechanism
Insulin travels through the blood and binds to its target cells, which can be myocytes or adipocytes. The
binding of insulin to its receptor signals vesicles with the glucose transporter protein (GLUT4) to mobilize and
fuse with the membrane. Glucose can then enter the cell. More detailed steps:
- The insulin receptor has two alpha-subunits and two B-subunits. Insulin binds to the alpha-subunits
located at the exterior of the cell, this causes a change in conformation of B-subunits.
- The change in conformation causes auto-phosphorylation of various tyrosine residues in the B-
subunits. The tyrosine residues will be phospho-tyrosine, which will act as second messengers.
- Phospho-tyrosine will drive the transformation of insulin receptor substrate 1 (IRS-1) into an active
form by phosphorylation.
- The active IRS-1 will bind to the enzyme PI-3K and activate it.
- The active PI-3K will act on PIP2 and phosphorylates it, this causes a conversion into PIP-3.
- PDK-1 will bind to PIP-3 and gets activated.
- Activated PDK-1 will recruit PKB and phosphorylates it.
- The phosphorylated PKB will promote clathrin-aided movement of GLUT4, this will cause the vesicles
containing GLUT4 to migrate and fuse with the cell membrane by which glucose from blood can enter
the target cells.
1. What is the difference between type 1 and type 2 diabetes?
Causes T2DM
Mostly a family history of type 2 diabetes, but also obesity, sedentary lifestyle, increasing age and a bad diet
Prevalence
The global prevalence of diabetes* among adults over 18 years of age rose from 4.7% in 1980 to 8.5% in 2014
(WHO). The number of people with diabetes rose from 108 million in 1980 to 422 million in 2014.
Approximately 90-95% has diabetes type 2. The majority living in low-and middle-income countries, and 1.6
million deaths are directly attributed to diabetes each year.
Symptoms T2DM
- peeing more than usual, particularly at night
- feeling thirsty all the time
, - feeling very tired
- losing weight without trying to (because protein and fat utilized as alternative energy source to
glucose)
- itching around your penis or vagina, or repeatedly getting thrush
- cuts or wounds taking longer to heal
- blurred vision (alters shape of the lens)
- Increased urine output (when glucose levels exceed threshold 9-10 mmol/l the kidney eliminates
glucose through increased urine production = excessive water loss.
Diagnosis
- Glycated hemoglobin (A1C) test. Most commonly used! This blood test indicates your average
blood sugar level for the past two to three months. Normal levels are below 5.7 percent, and a
result between 5.7 and 6.4 percent is considered prediabetes. An A1C level of 6.5 percent or
higher on two separate tests means you have diabetes.
- Random blood sugar test. Blood sugar values are expressed in milligrams per deciliter (mg/dL) or
millimoles per liter (mmol/L). Regardless of when you last ate, a blood sample showing that your
blood sugar level is 200 mg/dL (11.1 mmol/L) or higher suggests diabetes, especially if you also
have signs and symptoms of diabetes, such as frequent urination and extreme thirst.
- Fasting blood sugar test. A blood sample is taken after an overnight fast. A reading of less than
100 mg/dL (5.6 mmol/L) is normal. A level from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) is
considered prediabetes. If your fasting blood sugar is 126 mg/dL (7 mmol/L) or higher on two
separate tests, you have diabetes.
- Oral glucose tolerance test. This test is less commonly used than the others, except during
pregnancy. You'll need to fast overnight and then drink a sugary liquid at the doctor's office.
Blood sugar levels are tested periodically for the next two hours. For this test, you fast overnight,
and the fasting blood sugar level is measured. Then you drink a sugary liquid, and blood sugar
levels are tested periodically for the next two hours. A blood sugar level less than 140 mg/dL (7.8
mmol/L) is normal. A reading between 140 and 199 mg/dL (7.8 mmol/L and 11.0 mmol/L)
indicates prediabetes. A reading of more than 200 mg/dL (11.1 mmol/L) after two hours indicates
diabetes.
2. How does insulin regulation work in healthy individuals?
Insulin production and secretion in liver
The islets of Langerhans are scattered throughout the pancreas, these are endocrine cells and make
up 2% of the total liver mass. The islets of Langerhans consist of:
, - B-cells: nearly three-quarter of the islet cells, produce insulin and amylin.
- Alpha-cells: 20% of islets cells, secrete glucagon
- PP cells: rare cells which produce pancreatic polypeptide
Insulin is synthesized as an inactive prohormone and is activated prior to secretion.Before secretion the
proinsulin is cleaved into insulin and C-peptide. There are several factors which can trigger secretion:
- Increased plasma glucose: glucose plasma concentrations greater than 100 mg/dL is a major stimulus.
Glucose absorbed from the small intestine reaches the pancreatic B-cells where it is taken up by
GLUT2 transporters. With more glucose available as substrate ATP production increases and ATP-
gated K+ channels close. The cell depolarizes, voltage gated Ca2+ channels open and Ca2+ entry
initiates exocytosis of insulin.
- Increased plasma amino acids
- Feedforward effect of GI hormones: 50% of insulin secretion is stimulated by GLP-1 and GIP, these
are incretin hormones produced by cells of the ileum and jejunum in response to nutrient absorption.
The incretins travel through the circulation to the B-cells and may reach them even before glucose is
absorbed. The anticipatory release of insulin prevents a sudden surge in plasma glucose
concentrations when the meal is absorbed.
- Nervous system
- Parasympathetic activity: increases during and following a meal and stimulates insulin
secretion
- Sympathetic activity: insulin secretion is inhibited by sympathetic neurons, (nor)epinephrine
inhibits insulin secretion and switches metabolism to gluconeogenesis to provide extra fuel
for the nervous system and muscles.
, Insulin receptor mechanism
Insulin travels through the blood and binds to its target cells, which can be myocytes or adipocytes. The
binding of insulin to its receptor signals vesicles with the glucose transporter protein (GLUT4) to mobilize and
fuse with the membrane. Glucose can then enter the cell. More detailed steps:
- The insulin receptor has two alpha-subunits and two B-subunits. Insulin binds to the alpha-subunits
located at the exterior of the cell, this causes a change in conformation of B-subunits.
- The change in conformation causes auto-phosphorylation of various tyrosine residues in the B-
subunits. The tyrosine residues will be phospho-tyrosine, which will act as second messengers.
- Phospho-tyrosine will drive the transformation of insulin receptor substrate 1 (IRS-1) into an active
form by phosphorylation.
- The active IRS-1 will bind to the enzyme PI-3K and activate it.
- The active PI-3K will act on PIP2 and phosphorylates it, this causes a conversion into PIP-3.
- PDK-1 will bind to PIP-3 and gets activated.
- Activated PDK-1 will recruit PKB and phosphorylates it.
- The phosphorylated PKB will promote clathrin-aided movement of GLUT4, this will cause the vesicles
containing GLUT4 to migrate and fuse with the cell membrane by which glucose from blood can enter
the target cells.
