PHYSIOLOGY MANAWARI BATCH 2025

ENDOCRINE PANCREAS II: DIABETES MELLITUS

Luz A. Velasco, M.D / 7th Shifting
PHYCEUC ANS
OUTLINE 3. MODY Maturity Onset Diabetes in the Young
I. DIABETES MELLITUS
A. PATHOPHYSIOLOGICAL DEFECTS
B. TYPES OF DM • In both types of diabetes mellitus, metabolism of all the main food
C. CLASSICAL SYMPTOMS stuff is altered.
II. DIAGNOSIS OF DM • The basic effect of insulin deficiency or insulin resistance on
A. URINARY GLUCOSE glucose metabolism is to prevent the efficient uptake and
B. FASTING BLOOD GLUCOSE AND INSULIN utilization of glucose by most cells of the body, except those of
LEVELS the brain.
C. GLUCOSE TOLERANCE TEST • As a result, blood glucose concentration increases, cell
D. ORAL GLUCOSE TEST utilization of glucose falls increasingly lower, and utilization of
E. INCRETIN EFFECT
fats and proteins increases.
III. TYPE I DM
IV. TYPE II DM
V. RECENT DEVELOPMENTS IN DM
A. OMINOUS OCTET C. CLASSICAL SYMPTOMS
B. EGREGIOUS ELEVEN
VI. INSULIN RESISTANCE 1. Polydipsia and Polyuria
A. ADIPOSE TISSUE → Polyuria (excessive urine excretion), intracellular
B. ADIPONECTIN and extracellular dehydration
C. REGULATION → Polydipsia (increased thirst) are classic symptoms
D. APPROACH TO GLYCEMIC CONTROL of diabetes.
VII. APPENDIX → Very high levels of blood glucose (sometimes as
high as 8 to 10 times normal → increased osmotic
pressure in ECF → osmotic transfer of water out of
I. DIABETES MELLITUS the cells → Dehydration → Osmotic Diuresis
• Syndrome of impaired carbohydrate, fat, and protein → overall effect: massive loss of fluid → dehydration
metabolism → compensatory dehydration of ICF
• Chronic high blood glucose → Frequent urination kaya mauuhaw ka
• Caused by either lack of insulin secretion or decreased
sensitivity of the tissues to insulin. 2. Polyphagia and Pound (unexplained weight loss)
• Group of metabolic disorders characterized by → Failure to use glucose for energy → increased
hyperglycemia resulting from defects in insulin secretion, utilization and decreased storage of proteins and
insulin receptors or both. fat
→ Person with severe untreated DM experiences
A. PATHOPHYSIOLOGICAL DEFECTS rapid weight loss and asthenia (lack of energy)
1. Insulin deficiency despite eating large amounts of food (Polyphagia)
→ Result of cellular-mediated autoimmune → If not treated → wasting of body tissues and death
destruction of β-cells of the pancreas within a few weeks.
2. Insulin resistance → Hindi carbs (glucose) ang ginagamit ng katawan
→ Occurs when your cells stop responding to the mo for energy kaya pumapayat kahit kain nang
hormone insulin kain.
3. Ominous octet
→ Eight different defects in sugar metabolism (Type 2
diabetes
4. Egregious eleven
→ Six mechanisms that injure the β-cells and five
results of injury leading to hyperglycemia

B. TYPES OF DIABETES MELLITUS

1. Type I Diabetes Mellitus
→ Also known as:
▪ Insulin Dependent Diabetes Mellitus (IDDM)
▪ Juvenile onset diabetes mellitus
▪ Brittle diabetes
▪ Ketosis-prone diabetes mellitus
→ injury to β-cells of the pancreas or diseases that
impair insulin production can lead to type 1
diabetes
2. Type II Diabetes Mellitus
→ Also known as:
▪ Non-insulin dependent diabetes mellitus
▪ Adult type/maturity onset diabetes mellitus
▪ Stable diabetes
▪ Ketosis-resistant diabetes
▪ Receptor-deficient diabetes mellitus
→ initially caused by decreased sensitivity of target Table 1.1 Clinical Characteristics of Patients with Type 1 and 2 DM
tissues to the metabolic effect of insulin.

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 PHYSIOLOGY MANAWARI BATCH 2025

ENDOCRINE PANCREAS II: DIABETES MELLITUS

Luz A. Velasco, M.D / 7th Shifting
PHYCEUC ANS
II. DIAGNOSIS OF DM • Normal: fasting blood glucose level rises from about 90
mg/100 ml to 120 to 140 mg/100 ml and falls back to below
normal in about 2 hours.
NORMAL Pre-Diabetes Diabetes → Diabetic Patient: fasting blood glucose concentration is
(IFG and IGT) Mellitus almost always above 110 mg/100 ml and often is above 140
FPG (Fasting <100 mg/dl 100-125 mg/dl >or= 126 mg/dl mg/100 ml. In addition, results of the glucose tolerance test
Plasma (5.6 mmol/L) (5.6 to 6.9 (7 mmol/L) are almost always abnormal.
Glucose) mmol/L) → Persons with diabetes exhibit a much greater than normal
rise in blood glucose level, and their glucose level falls back
2hrPG <140 mg/dL 140-199 mg/dL ≥= 200 mg/dL to control level only after 4 to 6 hours, furthermore, it fails to
(7.8 mmol/L) (7.8 -11.0 (11.1 mmol/L) fall below the control level.
mmol/L)
→ The slow fall of this curve and its failure to fall below the
Table 1.2 Diagnostic Tests for DM
control level demonstrate that:
• HBA1c level: > 6.4 ▪ normal increase in insulin secretion after ingestion does
→ amount of erythrocytes or RBCs which are not occur, or
glycosylated ▪ the person has decreased sensitivity to insulin.
→ Diagnosis of DM can be established in the basis of such a
curve, and type 1 and type 2 DM can be distinguished from
A. URINARY GLUCOSE
each other by measurements of plasma insulin, with plasma
• Normal: undetectable amounts of glucose insulin being low or undetectable in type 1 diabetes and
• Diabetic patient: loses glucose in urine in proportion to the increased in type 2 diabetes.
severity of disease and the intake of carbohydrates

Figure 2.1 Urinary Glucose

B. FASTING BLOOD GLUCOSE AND INSULIN LEVELS

Table 2.3 Categories of FPG ang OGT

D. ORAL GLUCOSE TOLERANCE TEST (OGTT)

Table 2.2 Diagnostic Criteria for DM
• Fasting blood glucose (Guyton)
→ Early morning (normal): 80-90 mg/100 mL
→ 110 mg/100 mL – upper limit of normal; FBS above this
value → DM or ↑ insulin resistance
• Type 1 Diabetes
→ Plasma insulin levels are very low / undetectable during
fasting and even after a meal
• measurement of the ability of:
→ β-cells to secrete insulin
→ insulin to lower blood glucose
• normal person’s rise in blood glucose after drinking the
solution is reversed to normal in 2 hours; plasma insulin will
have a spike and then return to normal
• diabetic patients will have a big increase in the rise of blood
sugar and will not return to normal after ingestion; plasma
insulin will not have a change despite the ingestion of
glucose solution, consistently low levels of insulin

• Type 2 Diabetes
→ Plasma insulin concentration may be sevenfold higher than
normal and usually increases to a greater extent after
ingestion of standard glucose load during a glucose
tolerance test

C. GLUCOSE TOLERANCE TEST

• After ingestion of 1 gram of glucose per kilogram of body
weight:
Figure 2.2 Plasma Insulin

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 PHYSIOLOGY MANAWARI BATCH 2025

ENDOCRINE PANCREAS II: DIABETES MELLITUS

Luz A. Velasco, M.D / 7th Shifting
PHYCEUC ANS
E. INCRETIN EFFECT
• The increased stimulation of insulin secretion elicited by oral
as compared with intravenous administration of glucose
under similar plasma glucose levels
• Due to the stimulation of incretin hormones by glucose

Figure 3.1 Consequences of Uncorrected Deficiency in Type 1 DM

IV. TYPE II DM

• Mature onset diabetes mellitus

Figure 2.3 Measurement of the Incretin Efffect, OGTT and Matched
IV Infusion
• Figure shows that oral ingestion of glucose increases the
stimulation of insulin secretion.
• Previously non-insulin dependent but it is now a misnomer
• Β cell can be destroyed in later stages, slow to develop
• Genetic factors are significant, occurs most often in people who
are overweight
• Decreased sensitivity to insulin or an insulin resistance
→ part of cascade of disorders called the “metabolic
syndrome”
→ some of the features include:
▪ obesity, especially accumulation of abdominal
fat
▪ insulin resistance
▪ fasting hyperglycemia
▪ lipid abnormalities (e.g. ↑ blood triglycerides) and
↓ blood high- density lipoprotein-cholesterol
▪ hypertension
→ all of the features of the metabolic syndrome are closely
related to the accumulation of excess adipose tissue in the
abdominal cavity around the visceral organs
• do not usually develop ketoacidosis
• may have high blood [insulin] or normal [insulin]

Figure 2.4 Decreased Incretin Effect in Patients with Type 2 DM

• Figure shows that patients with Type 2 DM has a reduced

incretin effect, thus decreasing the stimulation of insulin
secretion.

III. TYPE I DM
• Juvenile diabetes; present in young patients
• Lack of insulin secretion caused by:
→ injury to β-cells (= cannot produce insulin; thus called
insulin-dependent diabetes mellitus)
→ viral infections or autoimmune disorders that lead to the
destruction of β-cells
→ genetics – degeneration of β-cells without any
underlying causes
• Without insulin, glucose cannot enter the muscles and
adipocytes
• rate of fat synthesis lags behind the rate of lipolysis
→ fatty acids are converted to ketone bodies ->
ketoacidosis
Table 3.1 Comparison of Type I and II DM
• Increased blood glucagon
→ stimulating glycogenolysis in the liver

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 PHYSIOLOGY MANAWARI BATCH 2025

ENDOCRINE PANCREAS II: DIABETES MELLITUS

Luz A. Velasco, M.D / 7th Shifting
PHYCEUC ANS
HYPOGLYCEMIA → angiotensinogen
• seen in prediabetic → TNF-α
• CAUSES: → resistin
→ secondary to over secretion of insulin → leptin
→ secondary to reactive hypoglycemia • obesity induces inflammatory changes in adipose tissue with
▪ caused by exaggerated response to a rise in blood release of inflammatory cytokines and altered production of
glucose adipokines -> insulin resistance
▪ occurs in people who are genetically predisposed
to Type II diabetes
• glucagon dysregulation
• patients under exogenous insulin administration can
experience hypoglycemia

V. RECENT DEVELOPMENT IN DIABETES

A. OMINOUS OCTET
• Increased lipolysis because of the following:
→ Insulin resistance in muscle resulting in
decrease glucose uptake
→ Insulin resistance in liver resulting also in Figure 6.1 Adipocyte
decrease glucose uptake • Preadipocyte differentiate into large insulin- resistant
→ Β-cell decline resulting to decrease insulin adipocyte that will secrete inflammatory cytokines and recruit
secretion macrophages that will further induce more inflammation in
→ Increased free-fatty acid levels in the blood adipocytes; increasing insulin resistance.
from fat cell breakdown • ↑ weight gain = ↑ insulin resistance
→ Loss of incretin function from the gut • enlarged fat depots contain ↑ large, insulin- resistant
→ Increased activity of α-cells in the pancreas adipocytes
→ Increased glucose re-absorption by the kidneys
via SGLT2 transporter
→ Insulin resistance in the brain resulting in
neurotransmitter dysfunction

B. EGREGRIOUS ELEVEN
• β-cell centric construct; decrease insulin common
denominator, 11 pathways of hyperglycemia
→ Pancreatic cell beta destruction leading to
decrease function and mass which results to
decrease insulin secretion (Treatment: Figure 6.2 Adipocyte
Incretins, Ranolazine)
• Insulin-resistant adipocytes secrete multiple signaling
→ Glucagon secretion due to alpha cell defect molecules linked with inflammation and insulin resistance.
(Incretins, Pramlintide)
→ cytokines released counteract the effect of insulin
→ Decrease incretin effect (Incretin) and correspond to inflammatory effects
→ Liver, muscle, adipose insulin resistance (TZDs, → TNF α
Metformin)
→ resistin – increases resistance
→ Neurotransmitter dysfunction resulting to
→ free fatty acids – toxic to endothelial cells, causing
increase appetite (Incretins, Dopamine-agonist-
vascular inflammation
QR, appetite suppressants)
→ leptin – increases appetite
→ Increased absorption of colon because of
→ angiotensin II – increases blood pressure
disturbance in colonic microbiota (Probiotics,
→ PAI-1 – causes thrombogenesis
Incretins, Metformin)
→ adiponectin – protective **, decreased levels
→ Immune dysregulation/inflammation (Incretins,
Anti-inflammatories, Immune modulators)
→ Increase absorption in intestine but decreased
reabsorption in kidneys
▪ GLP1 Agonists for stomach and
intestine; pramlinitide, AGI
▪ SGLT2 inhibitors for kidneys

VI. INSULIN RESISTANCE

A. ADIPOSE TISSUE
• endocrine organ aside from storage
• secretes adipocytokines:
→ adiponectin
Figure 6.3 Adipocytokines
→ IL-6
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 PHYSIOLOGY MANAWARI BATCH 2025

ENDOCRINE PANCREAS II: DIABETES MELLITUS

Luz A. Velasco, M.D / 7th Shifting
PHYCEUC ANS
C. REGULATION
• PPARγ is the master regulator of pre-adipocyte
differentiation
• Thiazolidinediones (TZD) or Glitazones
→ PPAR agonist
→ antidiabetic drug
→ has beneficial effects against insulin resistance
→ promotes pre-adipocyte differentiation into insulin-
responsive small adipocytes and prevents
differentiation into insulin- resistant large
adipocytes
→ blocks lipolysis and inflammatory cytokine release
→ pro-apoptotic for insulin-resistant adipocytes

Figure 6.4 Leptin and Energy Balance

B. ADIPONECTIN
• 249 AA hormone produced by adipocytes
• Decreases as visceral fat and BMI increases
• Low plasma levels highly associated with insulin resistance
and type 2 DM
• Receptors (1 and 2) in muscle, liver, and adipose tissue
• Actions synergistic with insulin Figure 6.6 TZDs and Adiponectin
• Signal transduction: AMPK activation
• Actions synergistic with insulin • Glitazone increase adiponectin -> reduces insulin
• Mode of Action: resistance in muscle and liver
→ FA oxidation (liver/muscle) • Adipose tissue : PPARγ , decrease adipocyte
→ ↑ glucose uptake (muscle)
→ ↓ gluconeogenesis (liver) D. HOLISTIC APPROACH TO GLYCEMIC CONTROL
→ other actions: inhibits vascular inflammation
• levels increased by activating PPARγ
HYPERGLYCEMIA IN TYPE II DM
→ PPAR agonist drugs increases adiponectin
reduction • Target the pathophysiologic defects in Type 2 Diabetes
• in IR, there is decreased adiponectin, decreased glucose • Neurotransmitter dysfunction
uptake and increased glucose output from the liver → GLP-1 receptor agonists – for incretin effect
• PPAR: nuclear peroxisome proliferator activating receptors → Amylin
→ PPARα – stimulates FA uptake / oxidation → Bromocriptine
→ PPARγ – stimulates pre-adipocyte differentiation • Impaired insulin secretion
(activation causes ↑ adiponectin) → Sulfonylurea – for ATP-dependent potassium channels
• Insulin resistance highly associated with visceral fat → Meglitinide
→ GPL-1 receptor agonists
→ DPP-4 inhibitors
• Increased glucagon secretion
→ GLP-1 receptor agonists
→ DPP-4 inhibitors
→ Amylin
• Increased hepatic glucose production
→ Metformin
→ Insulin
→ TZDs
• Increased lipolysis and reduced glucose uptake
→ Thiazolidinediones
• Increased glucose reabsorption
→ SGLT2 inhibitors / Gliflozins
• Decreased glucose uptake
Figure 6.5 Metabolic and Vascular Actions of Adiponectin → Metformin
→ Insulin
• ↑ insulin sensitivity in muscles and liver → TZDs
• ↓ vascular inflammation, atherosclerosis in the blood • Decreased incretin effect
vessels → Metformin

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 PHYSIOLOGY MANAWARI BATCH 2025

ENDOCRINE PANCREAS II: DIABETES MELLITUS

Luz A. Velasco, M.D / 7th Shifting
PHYCEUC ANS
→ α-Glucosidase inhibutors
→ Colesevetam
→ GLP-1 receptors

ORGAN ORGAN/TISSUE RESULTING RESULTING SIGNS AND SYMPTOMS

/TISSUE RESPONSES TO CONDITION OF CONDITION OF
INVOLVED INSULIN BLOOD URINE
DEFICIENCY
Liver, Decreased Hyperglycemia Glycosuria Polyuria
Adipose glucose uptake : t-max is threshold Dehydration → thirst
Tissue, and utilization for glucose is soft eyeballs
Muscle exceeded and goes
out of the urine
Liver ! Glycogenolysis Polydipsia
Fatigue Weight
Liver, Muscle ! Protein Osmotic diuresis loss
catabolism &
gluconeogenesis Polyphagia
Due to cell hunger
Liver, ! Lipolysis Lipidemia Ketonuria Acetone breath
Adipose (presence of lipids - Loss of Na+, K+; Hyperpnea (forced respiration)
Tissue, in the blood) Nausea / vomiting/ abdominal pain
Muscle ! Ketogenesis electrolyte and
Cardiac irregularities
acid-base
Ketoacidosis Central nervous system depression ;
imbalances
coma

REFERENCE
• Trans 2024

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