Diabetes Mellitus: Presentation By: Dr. Petrescu Elena Dr. Stanescu Raluca
Diabetes Mellitus: Presentation By: Dr. Petrescu Elena Dr. Stanescu Raluca
Diabetes Mellitus: Presentation By: Dr. Petrescu Elena Dr. Stanescu Raluca
Presentation by:
Dr. Petrescu Elena
Dr. Stanescu Raluca
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Biosynthesis of insulin
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Secretion of insulin
•Insulin secretion is stimulated by elevated glycemia
•Glucose enters the β cell via the GLUT2 transporter → it is metabolized through
glycolysis and Krebs cycle → the ATP levels within the cell increase → closing of the
ATP-sensitive K+ channels in the plasma membrane → membrane depolarization
•This leads to the opening of the voltage-gated Ca2+ channels in the plasma
membrane → influx of Ca2+ and increase in intracellular Ca2+ → this triggers the
release of insulin by exocytosis
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Factors that affect insulin secretion
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4. Intestinal hormones (incretins) - secreted by the intestinal cells after contact with
food
• GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic
peptide)
• They cause a rise in insulin levels in the blood before the rising of glycemia
• GLP-1 causes a transient decline in glycemia level after meals → its plasma half-life
is only 2 min because it is degraded by dipeptidyl peptidase-4 (DPP-4 - a peptidase
that removes proline-containing dipeptides from the N-terminus of polypeptides)
• Inhibitors of DPP-4 (known as gliptins) are a class of oral hypoglycemic drugs that
can be used to treat diabetes mellitus type 2
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Glucose homeostasis
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Metabolic actions of insulin
1. Effects on carbohydrate metabolism (exerted mainly in liver, muscle, and adipose)
•It increases glucose uptake (muscle, adipose) – by increasing the number of GLUT4
transporters in the plasma membrane
•It stimulates glucose degradation through glycolysis (liver, muscle)
•It stimulates glycogen synthesis (liver, muscle)
•It inhibits glycogen breakdown (liver, muscle)
•It inhibits gluconeogenesis (liver)
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The actions of insulin
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Combined effects of insulin and glucagon on substrate flow between
liver, adipose tissue and muscle
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Classification of diabetes mellitus
• Type 1 diabetes (insulin-dependent)
- results from β-cell destruction → insufficient insulin secretion
- it accounts for 5-10% of the diagnosed cases of DM
- it manifests before 20 years of age
- patients are prone to ketoacidosis
Type 2 DM
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Progression of blood glucose and insulin levels in patients with
type 2 DM
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Criteria for the diagnosis of diabetes mellitus
• Fasting plasma glucose ≥ 126 mg/dL (fasting = no caloric intake for at least 8h) at
more than one determination
or
• 2-h plasma glucose ≥ 200 mg/dL during an OGTT
or
• Hb A1c (glycated Hb) ≥ 6.5%
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Metabolic disturbances in DM
• The insulin deficiency leads to a decreased insulin/glucagon ratio
1. Carbohydrate metabolism
• ↓ glucose uptake in muscle and adipose tissue
• ↑ glucose production in the liver – stimulation of glycogenolysis and
gluconeogenesis
• => hyperglycemia; when it exceeds the renal threshold (180 mg/dL) → glycosuria
with osmotic diuresis and electrolyte depletion (polyuria→ polydipsia)
2. Lipid metabolism
• ↑ lipolysis in the adipose tissue => ↑ release of fatty acids => ↑ level of plasma
FFA (free fatty acids)
• ↑ uptake of FA in the liver => ↑ synthesis of triglycerides (TG) and VLDL =>
↑ level of plasma VLDL
• ↓ lipoprotein lipase (LPL) activity => ↓ catabolism of TG from chylomycrons and
VLDL => ↑ level of plasma TG
• From ↑ VLDL => ↑ LDL => ↑ level of plasma cholesterol 18
• ↑ activity of CETP (cholesterol ester transfer protein) => ↑ transfer of TG from
VLDL to HDL and of cholesterol esters (CE) from HDL to VLDL =>
- ↓ level of plasma HDL => ↑ atherogenic risk
- formation of LDL with ↑ CE (small dense LDL), which are more atherogenic
• Mainly in type 1 DM: the ↑ level of FA in the liver => ↑ amounts of acetyl-CoA
resulted from their oxidation => ↑ conversion to ketone bodies
- ↑ ketogenesis leads to ketonemia, ketonuria and ketoacidosis
3. Protein metabolism
• ↓ cellular uptake of amino acids and ↓ protein synthesis
• ↑ utilization of amino acids in gluconeogenesis
• Non-enzymatic glycosylation of proteins → negatively affects their structure and
function
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Metabolic disturbances in type 1 DM
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Metabolic disturbances in type 2 DM
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Markers for monitoring DM
• There is now clear evidence that in both type 1 and type 2 diabetes, the incidence
of long-term complications can be reduced by achieving tight control → this
requires meticulous monitoring of glycemic control
Fasting glucose
OGTT
Hb A1c, fructosamine
Microalbuminuria
Ketone bodies
Insulin, C peptide
Autoantibodies – to: insulin, β-cell of pancreatic islets, GAD
Total cholesterol, LDL-C, HDL-C, TG
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Fasting glycemia
• N = 70-110 mg/dL
• Monitoring of therapy is performed according to this parameter
• Especially in type 1 diabetic patients, insulin doses need to be frequently and
carefully adjusted on the basis of multiple daily blood glucose measurements
• Evaluates glucose clearance from the circulation after glucose loading under
defined conditions
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• OGTT → standard conditions for the patient:
- a minimum carbohydrate intake of 150 g/day for 3 days before the test
- a minimum 8-hour fast before testing
- exercise, smoking and emotional stress should be avoided during the test
• The test:
- blood and urine are collected for glycemia and glycosuria determination
- the glucose load: 75 g of glucose in 250 mL of water
- after 2 h blood is collected again for glycemia measurement
• Interpretation of results:
Glycemia
Fasting 2h
Normal < 110 < 140
IGT < 126 140-199
(prediabetes)
DM ≥ 126 ≥ 200
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Glycated hemoglobin (Hb A1c)
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Glycated albumin (fructosamine)
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Glycosuria
• Is a poor marker for DM
• The normal renal threshold for glucose is 180 mg/dL → in diabetic patients may be
increased
• Glycosuria may be associated with normal glycemia (renal glycosuria: decreased
renal threshold)
Microalbuminuria
• It allows the detection of nephropathy onset – when the level is > 300 mg/24 h
• Monitoring patients with DM for microalbuminuria is recommended – a rigorous
control of diabetes delays the onset and progression of nephropathy
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Ketone bodies
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Insulin and C-peptide
• Recommendations:
- to estimate the endogenous insulin secretion in a diabetic patient
- to detect the cause of hypoglycemia (e.g. insulinoma)
- to detect insulin resistance – when the subject has borderline or slightly increased
glycemia, or IGT at the OGTT, and insulin + C-peptide are increased
• The C-peptide measurement is more accurate than that of insulin due to a longer
plasma half-life (20-30 min), and it is imposed in patients who are on insulin
therapy or have insulin autoantibodies
• Insulin produced by the pancreas is extensively (approx. 50%) first-pass
metabolized by the liver → peripheral insulin levels may not accurately reflect
portal insulin secretion
• Peripheral C-peptide levels more accurately reflect portal insulin secretion (C-
peptide has negligible extraction by the liver)
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Autoantibodies
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Acute complications of DM
•Complication of type 1 DM
•Caused by conditions that increase the need for insulin: acute stress, infection,
trauma, excessive physical exercise – these are associated with an increased release of
hyperglycemiant hormones
•It can be the first manifestation of type 1 DM
•Marked hyperglycemia ( > 250-300 mg/dL) → glycosuria with osmotic diuresis → loss
of Na+, K+, and water → hypovolemia
•Water and electrolyte loss due to vomiting increases fluid depletion
•Significant dehydration
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• Increased lipolysis → ↑ plasma FFA →
↑ ketogenesis in the liver → ketonemia,
ketoacidosis and ketonuria, the odor of
acetone on the breath
• ↑ [H+] → they enter the cells by exchange
with K+ → hyperpotassemia
• Acidosis is partially compensated by
hyperventilation (Kussmaul’s respiration)
• ↓ pH, ↓ [HCO3-]
• ↑ anion gap – caused by the
accumulation of sodium salts of keto-
acids
• ↑ plasma urea – due to dehydration
(with decreased GFR) and protein
hypercatabolism
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2. Hyperglycemic hyperosmolar nonketotic coma (HHNC)
•Occurs in elderly patients with type 2 DM and with a compromised renal function →
they have important losses of water and electrolytes; usually is determined by stress
factors or major diseases
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Diabetic HHNC
ketoacidosis
Glycemia > 300 mg/dL > 600 mg/dL
Glycosuria positive positive
Anion gap (N: 8-16 > 16 < 16
mmol/l)
Plasma osmolality ≤ 320 > 350
(N ≤ 320 mOsm/kg)
Ketonemia /-uria ↑ / positive normal / negative
HCO3- (mmol/L) < 15 > 20
pH < 7.35 7.35-7.45
C-peptide < 0.7 normal/↑
(N: 0.7-1.8 μg/L)
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3. Hypoglycemia
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Major causes and clinical features of hypoglycemia
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Bibliography
Simon W Walker, Geoffrey J. Beckett, Peter Rae, Peter Ashby. Lecture Notes:
Clinical Biochemistry 9th Edition, Wiley- Blackwell, New Jersey, 2013
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