Diabetes Mellitus

Darweesh O. Chua
Cheley Marie Co
Diabetes Mellitus
Diabetes Mellitus
● Group of common metabolic disorders that share the phenotype of
hyperglycemia
● Factors contributing to hyperglycemia:
○ reduced insulin secretion, decreased
○ glucose utilization
○ increased glucose production
Epidemiology
● 1 in 14 Filipino adults lives with diabetes
● 2019, IDF
● 3,993,300 out of 63,265,700 filipino adult have diabetes
● 6.3 prevalence of diabetes in adults
● IDF projection: by 2030, number of adults with diabetes in PH will further
rise to 5,289,700 and aby 2045 7,267,400
Diagnosis
Screening
● Fasting plasma glucose or HbA1c
○ a large number of individuals who meet the current criteria for DM are
asymptomatic and unaware that they have the disorder
○ epidemiologic studies suggest that type 2 DM may be present for up to
a decade before diagnosis some
○ individuals with type 2 DM have one or more diabetes-specific
complications at the time of their diagnosis
○ treatment of type 2 DM may favorably alter the natural history of DM
○ diagnosis of prediabetes should spur efforts for diabetes prevention
Screening
ADA criteria for the Dx of diabetes
1. A1C ≥6.5%
OR
2. FPG ≥126 mg/dL (7 mmol/L)
OR
3. 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an
OGTT
OR
4. In a patient with classic symptoms of hyperglycemia or
hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1
mmol/L).
Regulation of Glucose Homeostasis
Insulin Secretion
 Type 1 Diabetes Mellitus
Immune-mediated destruction of
the pancreatic beta cells and
insulin deficiency
Can develop at any age
Pathophysiology - islet cell autoantibodies (ICAs)
- activated lymphocytes in the
islets, and peripancreatic lymph
nodes
- T lymphocytes that proliferate
when stimulated with islet
proteins
- release of cytokines within the
insulitis
Type 2 Diabetes Mellitus
Insulin resistance and abnormal
insulin secretion
- impaired insulin secretion
- insulin resistance
- excessive hepatic glucose
production
- abnormal fat metabolism
- systemic low-grade inflammation
Diabetes Mellitus:
Management and
Therapies
Overall Goals
● Eliminate symptoms related to hyperglycemia
● Reduce or eliminate the long-term microvascular and macrovascular
complications of DM
● Allow the patient to achieve as normal a lifestyle as possible
Lifestyle Management
Diabetes Self-Management Education and Support (DSMES)
● refers to ways to improve the patient’s knowledge, skills, and abilities
necessary for diabetes self-care and should also emphasize psychosocial
issues and emotional well-being
Nutrition Therapy
● high-quality, nutrient-dense with limits on carbohydrate intake required for
glycemic control and weight management
Lifestyle Management
Physical Activity
● ADA recommends 150 min/week (distributed over at least 3 days) of
moderate aerobic physical activity with no gaps longer than 2 days.
Psychosocial Care
● Depression, anxiety, or “diabetes distress,” defined by the ADA as “…
negative psychological reactions related to emotional burdens…in having to
manage a chronic disease like diabetes,” should be recognized and may
require the care of a mental health specialist
Management of
T1DM
Insulin Regimens
● Short-acting insulin analogues - injected just before (<10 min)
● Regular insulin - 30–45 min prior to a meal.

● In general, individuals with type 1 DM require:

○ 0.3-0.7 units/kg per day of insulin divided into multiple doses, with
approximately 50% of daily insulin given as basal insulin and 50%
as prandial insulin.
Immunopathology
Insulin Allergy
● Immediate type hypersensitivity, is a rare condition in which local or
systemic urticaria results from histamine release from tissue mast cells
sensitized by anti-insulin IgE antibodies
Immune Insulin Resistance
● Low titer of circulating IgG anti-insulin antibodies that neutralize the
action of insulin to a negligible extent develops in most insulin-treated
patients
Immunopathology
Lipodystrophy
● Injection of animal insulin preparations sometimes led to atrophy of
subcutaneous fatty tissue at the site of injection.
Management of
T2DM
DRUGS THAT PRIMARILY LOWER
GLUCOSE LEVELS BY THEIR ACTIONS ON
THE LIVER, MUSCLE, & ADIPOSE TISSUE

Biguanides,
thiazolidinedines
BIGUANIDES
BIGUANIDES
Metformin
METABOLISM AND EXCRETION:
● T ½ = 1.5-3 hrs
● Renally excreted
● eGFR
○ 60 - 45 mL/min per 1.73 m2 = SAFE
○ 45 - 30 mL/min per = USE CAUTIOUSLY
○ < 30 mL/min/1.73 m = CONTRAINDICATED!
Metformin
CLINICAL USE
● Insulin-sparing agent
● DOES NOT increase body weight
● DOES NOT provoke hypoglycemia
● Max dose: 2.55g/day
● w/
Metformin
Toxicities:
● Gastrointestinal
○ Anorexia, N/V, abdominal discomfort, diarrhea
● Vitamin B12 deficiency (prv: inc Ca intake)
● Lactic acidosis
○ Inc in conditions of tissue hypoxia, renal failure,
inc prod. Of LA

!!! temporarily halt on the day of radiocontrast

administration!!!
THIAZOLIDINEDIONES
THIAZOLIDINEDIONES
TOXICITIES
● Fluid retention
● ↑ risk of HF
● ↑ risk of MI (ROSI)
● ↑ risk of bone fractures
● Drug interactions: OCP, cyclosporine
DRUGS THAT PRIMARILY STIMULATE
INSULIN RELEASE BY BINDING TO THE
SULFONYLUREA RECEPTOR

KATP Channel modulators

Sulfonylureas, Non-sulfonylureas
(Meglitinides, D-phenylalanine derivatives)
INSULIN
SECRETAGOGUES
 SULFONYLUREAS
1ST GENERATION 2ND GENERATION

Chlorpropamide, Glyburide, Glipizide,

Tolazamide, Tolbutamide, Gliclazide, Glimepiride
Acetohexamide
● High potency
● Low potency ● Longer duration of action
● Large daily doses ● Small daily doses
● High risk for
hypoglycemia
● Fewer A/E, Di
SULFONYLUREAS

Toxicities:
● Hypoglycemia
● Skin rashes or
hematologic toxicity
● Weight gain
 Non-sulfonylureas
➔ Meglitinides
◆ Repaglinide
● S/E: hypoglycemia, secondary failure
➔ D-phenylalanine derivative
◆ Nateglinide
● promotes a more rapid but less-sustained secretion of
insulin than other available oral antidiabetic agents
● Fewer episodes of hypoglycemia.
DRUGS THAT AFFECT ABSORPTION OF
GLUCOSE

α-glucosidase inhibitors

Acarbose, Miglitol, Voglibose

α-GLUCOSIDASE
INHIBITORS
 α-GLUCOSIDASE
TOXICITIES INHIBITORS
● flatulence, diarrhea, and abdominal pain
● Increase ALT, AST
DRUGS THAT MIMIC INCRETIN EFFECT
OR PROLONG INCRETIN ACTION

GLP-1 agonists, DPP-4

inhibitors
 GLP-1 RECEPTOR
AGONISTS
● Exenatide, liraglutide, albiglutide, and dulaglutide
● Used in combination with metformin or a sulfonylurea for
treatment of type 2 diabetes
● A/E: N/V, fatal acute pancreatitis

*GLUcagon like pepTIDE

 DPP-4 inhibitors
● Sitagliptin, saxagliptin, linagliptin, alogliptin, and vildagliptin
● Used in combination with metformin or a sulfonylurea for
treatment of type 2 diabetes
● A/E: headache, nasopharyngitis, and URTIs

*dipeptidyl pePTidase-4 INhibitors

SODIUM-GLUCOSE CO-TRANSPORTER 2
(SGLT2) INHIBITORS

-gliflozin
 (SGLT2) INHIBITORS
● Canagliflozin, dapagliflozin, and empagliflozin
● Used in combination with metformin or a sulfonylurea for
treatment of type 2 diabetes
● A/E: headache, nasopharyngitis, and URTIs
● CI: eGFR <45 mL/min/1.73 m2

*dipeptidyl pePTidase-4 INhibitors

OTHER HYPOGLYCEMIC DRUGS

Pramlintide, colesevelam,
bromocriptine
 OTHER HYPOGLYCEMIC
DRUGS
● Pramlintide - injectable synthetic analog of amylin
○ suppresses glucagon release, slows gastric emptying, and works in
the CNS to reduce appetite
○ A/E: hypoglycemia and gastrointestinal disturbances
● Colesevelam
○ A/E: gastrointestinal complaints
● Bromocriptine - dopamine agonist
 INSULIN THERAPY
GENERAL
IN T2DM
PRINCIPLES
 Generally provided in three ways:

➢ As a basal supplement with an intermediate-acting to long-acting preparation

➢ As a pre-meal bolus dose of short-acting or rapid-acting insulin to cover the extra

requirements after food is absorbed

➢ As a premixed combination of intermediate-acting and short-acting or rapid-

acting insulin
Physiologic insulin replacement

❖ Insulin is secreted in a
pulsatile manner
❖ Intensive insulin therapy
➢ basal insulin + short-
acting or rapid-acting
insulins ≥ 3 times daily
before meals
DISADVANTAGES
❖ Weight gain
❖ Hypoglycemia
Monitoring Glycemia
❖ Glycated hemoglobin (A1C)
➢ ≤ 7.0 percent
❖ Blood glucose monitoring
➢ FBS of 80 to 130 mg/dL AND postprandial
glucose (90-120 minutes after a meal) < 180
mg/dL
➢ higher fasting glucose target - older patients, w/
CKD, or those with other risk factors for
hypoglycemia
WHEN TO INITIATE INSULIN?
❖ Severe hyperglycemia on presentation
➢ Symptomatic or severe hyperglycemia with ketonuria
➢ RBS consistently >300 mg/dL but without ketonuria or
spontaneous weight loss, in whom type 1 diabetes is not likely
❖ Difficulty distinguishing type of diabetes
❖ Pancreatic insufficiency
❖ Persistent hyperglycemia on oral agents
 WHEN TO START?

➢ At the time of diagnosis

➢ Highly motivated patients with A1C near target (ie,
<7.5 percent) 3-6-month trial of lifestyle modification
 CHOICE OF INITIAL GLUCOSE
LOWERING AGENT

➢ Mild hyperglycemia [126–199 mg/dL]: single, oral

glucose-lowering agent
➢ Moderate hyperglycemia [200–250 mg/dL]: ＞ 1 oral
agent or insulin
➢ Severe hyperglycemia [250–300 mg/dL] : Insulin
 CHOICE OF INITIAL THERAPY
➢ Asymptomatic, not catabolic
○ Metformin
■ Preferred initial therapy
● Glycemic efficacy
● Promoted modest weight loss
● Very low risk for hypoglycemia
● Favorable cost
 CHOICE OF INITIAL THERAPY
➢ Symptomatic, not catabolic
○ Ketonuria and/or weight loss present
● Insulin
○ Ketonuria and weight loss absent
● insulin/GLP-1 receptor agonists ± metformin
ACUTE DISORDERS
RELATED TO SEVERE
HYPERGLYCEMIA
 Diabetic Ketoacidosis
Pathogenesis ● Due to increased gluconeogenesis
and glycogenolysis, and impaired
peripheral glucose utilization
● Formerly a hallmark of type 1 DM
● Serum ketones (indicator of DKA)
should be measured in type 1 DM
when glucose is >300mg/dL
Symptoms ● Nausea, vomiting
● Thirst, polyuria
● Abdominal pain, dyspnea
Signs ● Tachycardia, tachypnea,
dehydration
● Kussmaul respirations
● Abdominal tenderness
● Decreased sensorium
Course ● Triad develops over 24 hours
● Uncontrolled hyperglycemia
● Metabolic acidosis
● Increased total body ketones
Hyperglycemic Hyperosmolar State
● Greater degree of dehydration and higher
endogenous insulin secretion (vs DKA)
● Primarily on older patients with type 2 DM
● Insulin levels inadequate to facilitate
glucose utilization by insulin-sensitive
tissues but adequate to prevent lipolysis and
ketogenesis
● Polyuria, weight loss
● Diminished oral intake
● Confusion, lethargy, coma
● Profound dehydration +/- hypotension
● Altered mental status
● NO nausea, vomiting, abdominal pain,
Kussmaul respiration (unlike DKA)
● Develops within several weeks
● Characterized by severe hyperglycemia,
hyperosmolality, dehydration
● Absence of ketoacidosis
Thanks!