1. Integration of Metabolism
Diabetes mellitus
Mulungushi University
School of Medicine and Health Sciences
Bachelor of Science in program
Biochemistry BMB 230
1
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
Dr. Masenga SK
2. To cover
•Metabolic effects of insulin and glucagon
•The feed/fast cycle
•Diabetes mellitus
•The Biochemistry of Diabetes Mellitus
•Forms of diabetes.
•Molecular aspects of glucose transport.
•Principles of treatment
•Obesity
2
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
3. Principals
• An adult human weighing 70 kg requires about 10–12 MJ
(2400–2900 kcal) from metabolic fuels each day.
• This requirement is met from
• carbohydrates (40–60%),
• lipids (mainly triacylglycerol, 30–40%),
• protein (10–15%),
• depending on whether the subject is in the fed or starving state and on
the intensity of physical work.
• When intake of fuels is consistently greater than energy
expenditure → storage fat → obesity
• When intake of fuels is consistently lesser than energy
expenditure → high turnover → emaciation and death.
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
3
4. Integrated metabolism
• Fed state: Glucose available → fuel for tissues
• Starvation : glucose spared for use by the CNS (which is largely
dependent on glucose) and the erythrocytes (which are wholly
reliant on glucose)
• Other tissues can utilize alternative fuels such as fatty acids and ketone
bodies
• As glycogen reserves become depleted, so amino acids arising from
protein turnover and glycerol arising from lipolysis are used for
gluconeogenesis.
• Insulin and Glucagon regulate
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
4
13. DIABETES MELLITUS
•Definition
•Is actually a group of metabolic diseases
characterized by hyperglycemia resulting from
defects in insulin secretion1, insulin action2, or both3.
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
13
15. •Therefore, the ADA/World Health
Organization (WHO) guidelines
recommend the following categories of
diabetes:
•Type 1 diabetes
•Type 2 diabetes
•Other specific types of diabetes;
MODY(Maturity onset diabetes of the
young)
•Gestational diabetes mellitus (GDM)
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
15
17. Classical Signs and symptoms:
•Polydipsia (Excessive Thirst)
•Polyphagia (Increased Food Intake)
•Polyuria (Excessive Urine Production)
•Rapid Weight Loss**
•Xerostomia (Dry Mouth)
•Hyperventilation
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
17
19. Type 1 diabetes
•result of cellular-mediated autoimmune destruction
of the cells of the pancreas, causing an absolute
deficiency of insulin secretion.
•constitutes only 10% to 20% of all cases of diabetes and
•This disease is usually initiated by
an environmental factor or
infection (usually a virus) in
individuals With a genetic
predisposition
commonly occurs in childhood
and adolescence.
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
19
20. •Characterized by :
•abrupt onset, insulin dependence,
hyperglycaemia, hyperosmolarity, low
pH(acidosis), ketonuria and ketonemia
•85% to 90% of individuals with fasting
hyperglycemia have 1 or more of these markers:
1. Islet cell autoantibodies,
2. Insulin autoantibodies,
3. glutamic acid decarboxylase autoantibodies,
4. tyrosine phosphatase IA-2 and IA-2B
autoantibodies.
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
20
21. Antibodies in T1DM
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
21
•Glutamic acid decarboxylase 65 (GAD)
•Protein tyrosine phosphatase islet
antigen-2 (IA2)
•Insulin.
•Zinc transporter 8 (ZnT8)
22. •Rationale For Diabetic Keto Acidosis
•In type 1, there is an absence of insulin with an excess of
glucagon. This permits gluconeogenesis and lipolysis to
occur.
•Patient’s lab profile presents with ketoacidosis tend to reflect
dehydration, electrolyte disturbances and acidosis.
•Acetoacetate, ᵝ-hydroxybutyrate and acetone are produced
from the oxidation of fatty acids.
• ketone bodies contribute to the acidosis.
•Lactate, fatty acids, and other organic acids can also
contribute to a lesser degree.
complications
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
22
23. •Bicarbonate and total carbon dioxide are usually decreased
due to Kussmaul respiration (deep respirations). This is a
compensatory mechanism to blow off carbon dioxide and
remove hydrogen ions in the process.
•The anion gap in this acidosis can exceed 16 mmol/L.
Serum osmolarity is high as a result of hyperglycemia;
•sodium concentrations tend to be lower (hyponatremia) due
in part to losses (polyuria) and in part to a shift of water
from cells because of the hyperglycemia.
•Grossly elevated triglycerides will displace plasma volume
and give the appearance of decreased electrolytes
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
23
24.
25. Type 1 Diabetes Mellitus
•The individual will be hyperglycemic, which can be severe.
• Glucosuria can also occur after the renal tubular transporter
system for glucose becomes saturated. (at plasma glucose
concentration ≥180 mg/dL (10mmol/l) in an individual with
normal renal function and urine output ).
• As hepatic glucose overproduction continues, the plasma
glucose concentration reaches a plateau around 300 to 500
mg/dL (17–28 mmol/L). Provided renal output is
maintained, glucose excretion will match the overproduction ,
causing the plateau.
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
25
26. •Hyperkalemia is almost always present as a result
of the displacement of potassium from cells in
acidosis. This is somewhat misleading because the
patient’s total body potassium is usually
decreased.
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
26
34. Insulin resistance
•Defined as the failure of target tissue to respond
normally to insulin
•Leads to :
• decreased uptake of glucose in muscle
• Reduced glycolysis
• Fatty acid oxidation in the liver
• Inability to suppress hepatic gluconeogenesis
• FATTY ACID EFFLUX out of adipose tissue
due to hormone sensitive lipoprotein lipase
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
34
35. ß-cell dysfunction
•Due to prolonged insulin resistance & eventually
hyperglycermia. Molecular mechanisms underlying ß-cell
dysfunction in type 2 diabetes are multifactorial & overlap
in many instances with those implicated in insulin
resistance.
•hence the excess NEFA & attenuated(reduced) insulin
signaling (“lipotoxicity”) predispose to both insulin
resistance & ß-cell failure.
•Amyloid replacement of islets is a characteristic finding in
individuals with long standing type 2 diabetes & is present
in more than 90% of diabetic islets examined.
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
35
36. •In type 2, insulin is present, as is (at times)
hyperinsulinemia; therefore, glucagon is attenuated
(lowered/reduced) → Weight gain (lipogenesis)
•Fatty acid oxidation is inhibited in type 2. This
causes fatty acids to be incorporated into
triglycerides for release as very low density
lipoproteins (VLDL).
•This might predispose a patient to acute
pancreatitis, development of eruptive xanthomata
(cholesterol deposits) and atherosclerosis.
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
36
38. PATHOPHYSIOLOGY CHAGES THAT
EXPLAIN THE LONG TERM COMPLICATIONS
OF DIABETES.
•The molecular pathogenesis of chronic diabetes
complications-
1. Excessive reactive oxygen species production
2. Formation of advanced glycosylation end (AGE)
products
3. Sorbitol production via the aldose reductase
pathway
4. Protein kinase c activation
Mnemonic = RASP
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
38
40. 25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
40
Macrovascular complications (coronary artery
disease, peripheral arterial disease, and stroke)
Microvascular
complications (diabetic
nephropathy, neuropat
hy, and retinopathy)
42. Infections
• Leukocyte function is compromised and immune responses
are blunted. hyperglycaemia effects in infections:
• Chemo taxis reduced
• Inhibits leukocyte rolling & adherence & phagocytosis
• reduces macrophage activation
• Reduces activation of the complement activation (C5a) therefore
reducing the Mac pathway (membrane attack complex) that lyses
bacteria
• Urinary tract infections are problematic
• Diabetes may develop fatal fungal infection - mucormycosis
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
42
45. LABORATORY FINDINGS IN HYPERGLYCEMIA
1. Increased glucose in plasma and urine
2. Increased urine specific gravity
3. Increased serum and urine osmolality
4. Ketones in serum and urine (ketonemia and
ketonuria)
5. Decreased blood and urine pH (acidosis)
6. Electrolyte imbalance
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
45
47. Fasting blood glucose
• The FPG test is used to detect diabetes and prediabetes
• Fasting plasma glucose = 7.0 mmol/L
• Impaired fasting glucose = 5.6 to 6.9 mmol/L
• most common test used for diagnosing diabetes
• more convenient and less expensive.
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
47
48. Random blood glucose
• Symptoms of diabetes (polyuria, polydipsia, unexplained weight loss,
fatigue, blurred vision, polypagia, and sores that do not heal).
• Random blood glucose concentration >11.1 mmol/L .
• A repeat test can be done for confirmation
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
48
50. Oral Glucose Tolerance Test
• The OGTT can be used to diagnose diabetes, prediabetes, and gestational
diabetes.
• 2-hr postload glucose >11.1 mmol/L during an oral glucose tolerance test
(OGTT) is diabetes
• identifies more patients as having diabetes than the fasting plasma glucose
test,
• greater expense and complexity and lower reproducibility
• Rarely used
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
50
52. Glycated Hemoglobin - HbA1C
• Reflects the average blood glucose levels over the past 3 months
and does not show daily fluctuations.
• Reported as a percentage with threshold level of 6.5%.
• It does not require fasting and can be performed at any time of
the day.
• Hemoglobinopathies and conditions of altered red-cell turnover
can give unreliable results
• Racial and ethnic differences in glycated hemoglobin levels have
been reported for given ambient glucose levels.
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
52
53. Criteria for the Testing and Diagnosis of
Gestational Diabetes Mellitus
• Only high-risk patients should be screened for GDM.:
• age older than 25 years,
• overweight, strong family history of diabetes,
• history of abnormal glucose metabolism,
• history of a poor obstetric outcome,
• presence of glycosuria,
• diagnosis of PCOS, or a member of an ethnic/racial group
with a high prevalence of diabetes (e.g., Hispanic American,
Native American, Asian American, African American, Pacific
Islander).
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
53
54. Criteria for the Testing and Diagnosis of
Gestational Diabetes Mellitus
• The first step in screening for gestational diabetes
should be performance of fasting plasma glucose (as indicated
earlier) with a confirmation test if needed for diagnosis.
• In the absence of a positive confirmation, evaluation for
gestational diabetes in women with average or high-risk
characteristics should follow one of two approaches.:
• The one-step approach would be the im-mediate
performance of a 3-hour OGTT without prior screening.
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
54
56. Risk factors
• BMI
• Family history
• Age
• Physical activity
• Sedentary lifestyle
• Diet
• Existing NCDs
• Drugs
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
56
58. reference
• Murray RK, Bender DA, Botham KM, Kennelly PJ, Rodwell
VW, Weil PA; Harper’s illustrated Biochemistry, 28th edition;
http://www.accessmedicine.com
58
25-Jan-22
Mulungushi University School of Medicine and Health
Sciences
