Medicine 2 (Endocrinology) I Lecture #6A

DIABETES MELLITUS
Dr. S. Sible | October 6, 2021

OUTLINE: Epidemiology & Worldwide Prevalence

I. OBJECTIVES ● The worldwide prevalence of DM has risen
II. DIABETES MELLITUS dramatically over the past two decades, from an
A. Definition estimated 30 million cases in 1985 to 415 million in
B. Epidemiology & Worldwide Prevalence 2017.
C. Studies & Trials
III. GLUCOSE HOMEOSTASIS
A. Insulin
IV. CLASSIFICATION OF DM
A. Etiologic Classification of DM
B. Gestational DM
C. Type 1 DM
D. Type 2 DM
V. DIAGNOSIS OF DM
A. Risk Factors
B. Screening
C. Diagnosis Figure 1. Worldwide prevalence of diabetes mellitus. Global
estimate is 415 million individuals with diabetes in 2017. Regional
VI. TREATMENT OF DM
estimates of the number of individuals with diabetes (20–79 years
A. Goals
of age) are shown (2017)
B. Lifestyle Intervention
C. Pharmacologic Therapy
● Based on the International Diabetes Federation
VII. REFERENCES
(IDF), they have projected that there will be 642
VIII. ABBREVIATIONS
million individuals who will have diabetes by the year
IX. APPENDIX
2040.
LEGEND: ● Although the prevalence of both type 1 and type 2
Black for powerpoint, red for audio lecture, blue for book DM is rising, the prevalence of type 2 DM is rising
much more rapidly, because of the increasing
number of obesity and reduced physical activity.
OBJECTIVES
● Type 1 diabetes has been increasing at a rate of 3–
● To discuss the diagnosis, classification, and 5% per year worldwide.
pathophysiology of DM ● Unfortunately, the significant rise in this estimated
● Discuss both acute and chronic complications prevalence is seen in Asia, in most developing
● Discuss the management of DM and its countries which includes the Philippines.
complications o The countries with the greatest number of
● Present the Philippine Clinical Practice Guidelines individuals with diabetes in 2015 are China
for Diabetes Mellitus (109.6 million), India (73 million), the United
States (30.3 million), Brazil (14 million), and the
DIABETES MELLITUS Russian Federation (9 million)
Definition
● A complex chronic illness requiring continuous
medical care with multiple factorial strategies beyond
glycemic control
● Different organizations, specifically the American
Diabetes Association (ADA) and the American
Association of Clinical Endocrinologist (AACE), has
been aggressive with regards to the revisions with
regards to the guidelines for physicians to have what
we call “Standard Care”
● Refers to a group of common metabolic disorders
that share the phenotype of hyperglycemia.
● Several distinct types of DM are caused by complex
interaction of genetics and environmental factors.
● Factors contributing to hyperglycemia includes:
o Reduced insulin secretion by the beta cells of the
pancreas
o Decreased glucose utilization by the basal and
adipose tissue
o Increased glucose production by liver
● The metabolic dysregulation associated with DM
causes secondary pathophysiologic changes in
multiple organ systems that impose a tremendous
burden on the individual with diabetes and on the
health care system Figure 2. Prevalence of Diabetes

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 Medicine 2 (Endocrinology) I Lecture #6A
DIABETES MELLITUS
Dr. S. Sible | October 6, 2021
● Where in the world is Diabetes prevalent?
o It has been shown in the different studies that the
Western Pacific Region has the highest
prevalence of diabetes particularly in the Pacific
Island Nation of Tokelau where 30% of the adult
population has diabetes.
● Diabetes is now a disease that affects 422M adults
worldwide, 187M of them do not even know that they
have the disease according to the IDF review
published last Nov 14, 2012.
● Approximately 25% of the individuals with diabetes
in the United States were undiagnosed; globally, it is
estimated that as many as 50% of individuals with
diabetes may be undiagnosed. The prevalence of
DM increases with age.
● The prevalence of diabetes is similar among men
and women, but diabetes-related mortality rates are
higher in men compared to women.
● Diabetes is a major cause of mortality. In recent
years, diabetes has been listed as the seventh
leading cause of death in the United States, but
several studies indicate that diabetes-related deaths
are likely underreported.
Studies & Trials
Diabetes Control and Complications Trial
● It has been shown in several trials that achieving
good glycemic control by reduction in HbA1c would
lead to the reduction in the microvascular
complications as well as macrovascular
complications.
● This has been proven by a landmark trial that is the
Diabetes Control and Complication Trial (DCCT)
done 1983 – 1993.
● Clinical Questions:
o Primary Prevention: Will an intensive treatment
program designed to achieve glycemic control as
close to non-diabetic range as safely possible
prevent or delay the appearance of early
background retinopathy?
o Secondary Prevention: Will such an intervention
prevent the progression of early retinopathy to
more advanced forms of retinopathy?
● This trial provided definitive proof that reduction in
chronic hyperglycemia can prevent many of the
complications of Type 1 DM
o A randomized trial = 1,400 individuals with Type
1 DM
o Demonstrated a reduction:
■ Nonproliferative and proliferative retinopathy
= 47%
■ Microalbuminuria = 39% reduction
■ Nephropathy = 54% reduction
■ Neuropathy = 64% reduction
o Intensive group (7.3%)
o Conventional group (9.1%)
● DCCT is a trial between intensive and conventional
therapy
● It shows there was a Relative Risk Reduction (RRR)
in the different New-Onset Complications:
o Retinopathy – 76%
o Nephropathy – 54%
o Neuropathy – 60%
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● Another landmark study that has proven that
reduction in HbA1c can lead to reduction in the
microvascular and macrovascular complications
● Demonstrated that each percentage point reduction
in A1c was associated with a 35% reduction in
microvascular complications
● Included in the study: more than 5000 individuals
with type 2 diabetes and they were followed up for
more than 10 years
● A randomized trial wherein patients were divided
into:
o Intensive group
▪ Received combination of insulin, an oral anti-
diabetic agent, a sulfonylurea, or metformin
▪ Goal was reduction of A1c to 7%
o Conventional group
▪ Put on dietary modification and
pharmacotherapy
▪ Goal was reduction of A1c to 7.9%
● Major findings:
o Strict blood pressure control significantly
reduced both macro and microvascular
complications
o Beneficial effects of BP control were greater than
the beneficial effects of glycemic control
o Lowering BP to moderate goals (142/82 mmHg)
reduced the risk of DM-related death, stroke,
microvascular endpoints, retinopathy, and heart
failure between 32% and 56%
GLUCOSE HOMEOSTASIS
● Glucose homeostasis reflects a balance between
energy intake from ingested food, hepatic glucose
production (gluconeogenesis), and peripheral tissue
glucose uptake and utilization.
● Organs that contribute to glucose utilization,
production and storage.
o Pancreas
▪ Alpha cells – Glucagon
▪ Beta cells – Insulin
➢ Insulin promotes storage in the liver by
stimulating glycolysis and
glycogenolysis and these store glucose
as glycogen
o Liver
o Brain
o Muscle and Fat
▪ Insulin stimulates the uptake of glucose in
the muscles and fat cells breaking it down to
energy
Insulin
● A protein
● Mature insulin has alpha and beta chain, made up of
several amino acids
● Packaged in the pancreas as proinsulin which
contains the C peptide
● Mature insulin contains intrachain disulfide bond
(Cysteine) as well as an intermolecular disulfide
bond
● Insulin is the most important regulator of this
metabolic equilibrium, but neural input, metabolic
signals, and other hormones (e.g., glucagon) result
in integrated control of glucose supply and utilization
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 Medicine 2 (Endocrinology) I Lecture #6A
DIABETES MELLITUS
Dr. S. Sible | October 6, 2021
CLASSIFICATION OF DM
● DM is classified on the basis of the pathogenic
process leading to hyperglycemia, as opposed to
earlier criteria such as age of onset or type of therapy
● There are two broad categories of DM, designated as
either type 1 or type 2 DM.
● However, there is increasing recognition of other
forms of diabetes in which the molecular
pathogenesis is better understood and may be
associated with a single gene defect. These
alternative forms may share features of type 1 and/or
type 2 DM.
Figure 3. Spectrum of glucose homeostasis and DM
Etiologic Classification of DM
I. Type 1 diabetes (immune-mediated β cell
destruction, usually leading to absolute insulin
deficiency)
● Previously called Insulin Dependent DM
(IDDM) or Juvenile onset DM
● Types:
a. Immune (Type 1A) – Immune-mediated
which has positive antibodies against the
beta cells
b. Idiopathic (Type 1B) – idiopathic; which
has negative antibodies against beta cells
II. Type 2 diabetes (may range from predominantly
insulin resistance with relative insulin deficiency to
a predominantly insulin secretory defect with
insulin resistance)
III. Specific Types of Diabetes
A. Genetic defects of beta cell development or
function characterized by mutations in:
● Hepatocyte nuclear transcription factor
(HNF) 4α Maturity-onset Diabetes of the
young type 1 (MODY 1)
● Glucokinase (MODY 2)
● HNF-1α (MODY 3)
● Insulin promoter factor-1, HNF-1β,
NeuroD1, and others leading to other
forms of MODY
● Insulin, subunits of ATP-sensitive
potassium channel leading to permanent
neonatal diabetes
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● Mutations in the Mitochondrial DNA
leading to diabetes
● Other pancreatic islet regulators/proteins
o such as KLF11, PAX4, BLK, GATA4,
GATA6, SLC2A2 (GLUT2), RFX6,
GLIS3
B. Transient neonatal diabetes
C. Diabetes caused by diseases of the exocrine
pancreas – pancreatitis, pancreatectomy,
neoplasia, cystic fibrosis, hemochromatosis,
fibrocalculous pancreatopathy, mutations in
carboxyl ester lipase
D. Genetic defects in insulin action, including type
A insulin resistance, Leprechaunism, Rabson-
Mendenhall syndrome, Lipodystrophy
syndromes
E. Diabetes can also be caused by
Endocrinopathies
● Such as acromegaly (which produces
growth hormone – it increases or
stimulates hepatic glucose production),
Cushing’s syndrome (from excess
glucocorticoids which is also an action-
stimulating hepatic glucose production),
glucagonoma, pheochromocytoma,
hyperthyroidism, somatostatinoma,
aldosteronoma
● These endocrinopathies can lead to DM
F. Drug- or Chemical-Induced Diabetes
● This is brought about by Glucocorticoids
● Vacor (a rodenticide), pentamidine,
nicotinic acid, diazoxide, β-adrenergic
agonists, thiazides, calcineurin and mTOR
inhibitors, hydantoins, asparaginase, α-
interferon, protease inhibitors,
antipsychotics (atypicals and others),
epinephrine
G. Infections – particularly congenital rubella,
cytomegalovirus, coxsackievirus.
H. Uncommon forms of immune-mediated
diabetes – “stiff-person” syndrome, anti-insulin
receptor antibodies.
I. Other genetic syndromes sometimes
associated with diabetes— Wolfram’s
syndrome, Down’s syndrome, Klinefelter’s
syndrome, Turner’s syndrome, Friedreich’s
ataxia, Huntington’s chorea, Laurence-Moon-
Biedl syndrome, myotonic dystrophy,
porphyria, Prader-Willi syndrome.
IV. Gestational diabetes mellitus (GDM)
Gestational Diabetes Mellitus
● Glucose intolerance develops during the second and
third trimester of pregnancy.
● Insulin resistance is related to the metabolic changes
of pregnancy, during which the increased insulin
demands may lead to impaired glucose intolerance
(IGT) or diabetes.
● Based on the ADA recommendation, diabetes
diagnosed during the first trimester of pregnancy
may be classified as preexisting pregestational
diabetes rather than GDM.
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 Medicine 2 (Endocrinology) I Lecture #6A
DIABETES MELLITUS
Dr. S. Sible | October 6, 2021

Type 1 Diabetes Mellitus Pathogenesis:

● Result of the interaction of genetic, environmental, ● Secondary to insulin resistance.
and immunologic factors ● Associated with impaired (not absent) ability to
● Destruction of the pancreatic beta cells leading to secrete insulin.
insulin deficiency ● Type 2 diabetes worsen with time.
● Develops most commonly before age 20 years of ● Type 2 DM is characterized by impaired insulin
age secretion, insulin resistance, excessive hepatic
● Long standing type 1 has small amounts of Insulin = glucose production, abnormal fat metabolism, and
determined by low C peptide levels. systemic low-grade inflammation.
● Genetic Consideration in Type 1 DM: ● Obesity, particularly visceral or central (as evidenced
o Concordance in identical twins ranges between by the hip-waist ratio), is very common in type 2 DM
40-60% (≥80% of patients are obese).
o Major susceptibility for Type 1 – Human
Leukocyte Antigen (HLA) region on chromosome DIAGNOSIS OF DM
6 Risk Factors
o Risk of developing Type 1 DM is increased ● Demographics
tenfold in relatives of individuals with the disease o Age: testing should be considered in all adults
though relatively low. aged ≥ 40 years old
o Family history: 1st degree relative with diabetes
Pathogenesis: o Sedentary lifestyle
● Inability of the pancreas to secrete insulin ▪ Less than 30 minutes of physical activity per
● Present abruptly, but not always day
● In older patients, they can be slow in onset more ▪ Walking less than 100 steps in 1 minute
often o Race or ethnicity
● Most, but not all, individuals with type 1 DM have ● Clinical Presentation
evidence of islet-directed autoimmunity. However, o Past medical history
some individuals who have the clinical phenotype of ▪ History of IGT or IFG
type 1 DM lack immunologic markers indicative of an ▪ Hypertension (BP ≥ 140/90 mmHg)
autoimmune process involving the beta cells and the ▪ Vascular disease (PAD, stroke, CAD, CVD)
genetic markers of type 1 DM. ▪ Schizophrenia
● These individuals are thought to develop insulin ▪ Pulmonary Tuberculosis
deficiency by unknown, nonimmune mechanisms, o Obstetrical history
and may be ketosis prone. ▪ GDM
▪ Has delivered a baby weighing ≥ 8 lbs.
Type 2 Diabetes Mellitus ▪ Polycystic Ovary Syndrome
● Insulin resistance and abnormal insulin secretion by ● Abnormal Physical Examination
the beta cells of the pancreas o Overweight or obese
● Latinos – greater insulin resistance o Waist circumference
● East and South Asians – more beta cell dysfunction ▪ Measured by placing a tape measure around
o Develop type 2 DM at a younger age and has the middle at a point halfway between the
lower BMI lowest rib and the iliac crest
o Strong genetic component o Waist-hip ratio
● Genetic Consideration in Type 2 DM: ▪ Hip circumference is measured around the
o Strong genetic component widest portion of the buttocks with tape
o Concordance in identical twins is between 70- measure parallel to the floor
90% o Acanthosis nigricans
o Individuals with a parent with Type 2 DM have an ▪ Discoloration or hyperpigmentation around
increased risk of diabetes (if both parents are the neck and axilla
diabetic – 40%) ● Laboratory Examination
o Genes that predispose to type 2 – variant of the o Serum HDL: < 35 mg/dL (0.9 mmol/L)
transcription factor 7–like 2 gene. o Serum triglycerides: > 250 mg/dL (2.82 mmol/L)
● What comes first in Type 2 Diabetes? o HbA1c of 5.7-6.4%
o Still debated/ unknown
o The worst defect is insulin resistance is present Table 1. Risk factor for diabetes based on abnormal
early physical examination
o Worsening likely due to loss of the ability to Abnormal PE
Parameter
compensate for insulin resistance by secreting Male Female
more insulin. BMI ≥ 25 kg/m2
≥ 90 cm or ≥ 80 cm or
Waist circumference
34 inches 31 inches
Waist-hip ratio ≥1 inch ≥ 0.85 inch
Acanthosis nigricans present

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 Medicine 2 (Endocrinology) I Lecture #6A
DIABETES MELLITUS
Dr. S. Sible | October 6, 2021

Table 2. Classification of Overweight and Obesity by Diagnosis

Various Reference Groups ● Fasting plasma glucose
Anthropometric WHO o Done after no caloric intake for at least 8 hours
WHO
Measures Asians* o ≥ 126 mg/dL (7.0 mmol/L)
BMI o Subjects with BORDERLINE fasting glucose
23 kg/m2 25 kg/m2
Overweight need a confirmatory 75-gram OGTT
BMI ● OGTT
25 kg/m2 30 kg/m2
Obese o Done like FBS, wherein patient needs to fast for
Male: 90 cm Male: 101.6 cm at least 8 hours, get FBS at 0 hr, then proceed
WC cutoff value with the 75 g OGTT, then another FBS is taken
Female: 80 cm Female: 88.9 cm
*in the Philippines, we are using the Asia Pacific guidelines at least 3 hours
▪ Value at 0 hr should be interpreted like FBS
▪ No dietary restrictions 3 days prior to test
o Sugar level 2 hours after drinking a sugary drink
(75 g of sugar) or anhydrous glucose which
contain 75 g of glucose
o ≥ 200 mg/dL (11.1 mmol/L)
● Random blood glucose concentration
o ≥ 200 mg/dL (11.1 mmol/L) with classic
symptoms of hyperglycemia (weight loss,
polyuria, polyphagia, polydipsia) or with signs
and symptoms of hyperglycemic crisis
Figure 4. Measuring the waist circumference
*Among ASYMPTOMATIC individuals with positive results,
any of the three tests should be REPEATED within two
weeks for confirmation

Table 3. Criteria for the Diagnosis of Diabetes Mellitus

Figure 5. Measuring waist to hip ratio

Screening Note: Laboratories NOT used for diagnosis of diabetes

● All individuals seen at the clinic or by any healthcare
provider should be evaluated ANNUALLY for risk
factors for diabetes and pre-diabetes
o If initial test is negative, repeat testing should be
done ANNUALLY
o According to guidelines, “We recommend repeat
testing annually for Filipinos with risk factors
owing to the significant prevalence and burden
of diabetes in our country”
● Universal screening using laboratory tests is NOT
recommended as it would identify very few
individuals who are at risk
● Who should we screen?
o 42/F, currently on Amlopidine, Telmisartan
medications – Yes!
o 35/M, with schizophrenia – Yes!
o 20/F, standing 5 feet and 7 inches, with vital
statistics of 36”-35”-38”
o 20/F with anthropometric measurements of:
weight 85 kg, height 5’5”, WC 35”, HC 40” – Yes!
● The following should undergo OGTT as initial test
screening
o IFG: 11-125 mg/dL or 5.6-6.9 mmol/L
o Previously diagnosed with CVD (CAD, stroke, or
PAD)
o High risk for CVD
o Diagnosis with metabolic syndrome
in the Philippines
● HbA1c
o Test for the chronicity of glycemic control
o This is the average blood glucose for the past
two to three months
o Not used for diagnosis unless you have a fasting
blood glucose of ≥ 126 mg/dL together with an
A1c of > 6.5
o A1c alone is not used in the Philippines because
we don’t have a standard kit yet for A1c
determination
● Capillary blood glucose
● Fructosamine
● Urine glucose
● Plasma insulin
*if a result is available upon consultation due to prior
testing, it should be interpreted with caution and should be
confirmed by any of the 3 tests that are considered
standard
TREATMENT
Goals
● The goals of therapy for type 1 or type 2 DM are to
o Eliminate symptoms related to hyperglycemia
o Reduce or eliminate the long term microvascular
and macrovascular complications of DM
o Allow patient to achieve as normal a lifestyle as
possible

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 Medicine 2 (Endocrinology) I Lecture #6A
DIABETES MELLITUS
Dr. S. Sible | October 6, 2021

● The care of an individual with either type 1 or type 2 Lifestyle Intervention

DM requires a multidisciplinary team including the ● Lifestyle intervention
primary care provider and/or the endocrinologist or o In the form of weight reduction and exercise
diabetologist, a certified diabetes educator, a o Weight loss and exercise improve insulin
nutritionist, a psychologist, and/or social worker sensitivity
● Treatment must be individualized o ADA recommends 150 min/week (distributed
over at least 3 days) of moderate aerobic
Table 4. Tangible and Surrogate Goals in Treating Diabetes physical activity with no gaps longer than 2 days
Tangible Goal Surrogate Goals o Resistance exercise, flexibility and balance
• Prevent worsening of • Low HbA1c training, and reduced sedentary behavior
diabetes o Main indicator of throughout the day are advised
• Prevent long term control ● Medical nutrition therapy (MNT) – optimal
complications • Good BP control coordination of caloric intake with other aspects of
• Good quality of life • Good lipid control diabetes therapy.
• A good cardiovascular • Low inflammatory o Components are similar for individuals with type
status markers 1 or type 2 DM and similar to those for the
• Avoid health care cost • Normal kidney general population – high quality, nutrient-dense
• Achieve a normal BMI function without specific focus on composition
• Ability to carry out • Normal liver function o Goals of MNT in type 1 DM is to coordinate and
physical activity match the caloric intake with the appropriate
amount of insulin
Table 5. Treatment Goals for Adults with Diabetes o Goals of MNT in type 2 DM should focus on
Index Goal weight loss and address the greatly increased
Glycemic Control prevalence of cardiovascular risk factors
HbA1c < 7.0 % o Hypocaloric diets and modest weight loss (5-7%)
Preprandial CPG 80-130 mg/dL (4.4-7.2 mmol/L) often result in rapid and dramatic glucose
Postprandial CPG < 180 mg/dL (10 mmol/L) lowering in individuals with new-onset type 2 DM
Blood pressure < 140/90 mmHg
*CPG – capillary plasma glucose Pharmacologic Therapy
Metformin
Table 6. ADA Treatment Goals for Glycemic Control adapted from ● Biguanides; representative drug of this class
ADA Standard of Care 2018; vol 41, suppl 1 ● Near universal acceptance as an initial drug therapy
More stringent for selected in the absence of contraindication of intolerance
individuals o Recommended as an initial pharmacologic
As close to
• Short duration of diabetes therapy unless there are complications to each
normal as
• Treatment with lifestyle and use
possible without o If goal is not achieved with metformin, we can
Metformin only
significant
• Long life expectancy add a second drug: DPP-4 inhibitor, insulin, or
hypoglycemia any drug with a different mechanism of action
• No significant cardiovascular
disease o If the patient at the onset presents with signs and
Less stringent for some patients symptoms of hyperglycemia (A1c of 9%), insulin
• Hypoglycemia unawareness should be initiated
• Limited life expectancy ● A generic drug with long history of use worldwide
(available for more than 50 years)
• Co-morbidity
HbA1c < 8.0 ● Activates AMP-dependent protein kinase and enters
• Long history of DM with
cells through organic cation transporters
minimal complications where
● Decreases hepatic glucose production and
control has been historically
increases muscle glucose uptake
difficult
o Metformin’s mechanism for reducing hepatic
glucose production is to antagonize glucagon’s
ability to generate cAMP in hepatocytes
● Advantage: weight neutral (does not cause weight
reduction or weight gain) and does not cause
hypoglycemia when used alone
● The major toxicity of metformin, lactic acidosis, is
very rare and can be prevented by careful patient
selection
● Evidence from several studies showed a reduction in
CV events and improved carotid IMT
● UKPDS showed a significant reduction in MI,
cardiac, and all cause mortality by 39, 50, and 36%
respectively when administered to obese patients
(weight > 120% of ideal)
Figure 6. Essential elements in comprehensive care of type 2 ● A1c reduction of 1-2%
diabetes
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 Medicine 2 (Endocrinology) I Lecture #6A
DIABETES MELLITUS
Dr. S. Sible | October 6, 2021
● Should not be used in patients with moderate renal
insufficiency (GFR <45 mL/min), any form of
acidosis, unstable CHF, liver disease, or severe
hypoxemia
Sulfonylureas
● Insulin secretagogues: agents that affect the ATP-
sensitive K+ channels
● MOA: increases insulin secretion by activating
potassium channels
● Examples: glipizide, glimepiride, gliclazide
o Glyburide, which is also known in the Philippines
as Glibenclamide – patients usually shy away
from using this drug because of hypoglycemia,
may have adverse interactions with cardiac
channels
o Glimepiride and glipizide can be given in a single
daily dose and are preferred over glyburide,
especially in the elderly
● Reduce both fasting and postprandial glucose
● In general, sulfonylureas increase insulin acutely and
thus should be taken shortly before a meal
● Advantages: well-tolerated and inexpensive
● Disadvantages: causes marked hypoglycemia
especially in elderly individuals, weight gain which
results from increased insulin levels and
improvement in glycemic control, some patients may
have sulfa allergy, low durability
● A1c reduction of 1-2%
● Studies about sulfonylurea shows:
o UGDP (1970) - increased CV mortality
(controversial)
o Retrospective and some prospective analyses of
databases support increased risk
o But, UKPDS, ADVANCE, ACCORD do not
support the increased CV risk
● Most sulfonylureas are metabolized in the liver to
compounds that are cleared by the kidney
o Use in individuals with significant hepatic or renal
dysfunction is not advisable
Dipeptidyl Peptidase–4 (DPP-4) Inhibitors
● MOA: block the degradation of endogenous GLP-1
and thus enhance the incretin effect
● Examples: sitagliptin (Januvia, Xelevia), alogliptin,
saxagliptin (Onglyza), linagliptin (Trajenta)
● Not really effective in lowering A1c
● Appear to have a preferential effect on postprandial
blood glucose
● Advantages: little or no hypoglycemia, weight neutral
● Disadvantages: urticarial, angioedema, pancreatitis
risk
● A1c reduction of 0.5-0.8%
● Studies show:
o Diabetes Care, Dec 2015
▪ Decreases triglycerides, may reduce high-
sensitivity C-reactive protein (hsCRP), may
improve endothelial function and improve
reduce ischemia-reperfusion in animals,
may reduce IMT
o CV outcome trials in high-risk patients (SAVOR-
TIMI and EXAMINE)
▪ No difference in outcome
▪ Slight increase in hospitalization for CHF
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o TECOS trial: 14671 patients who received either
sitagliptin or placebo
▪ No difference in CV events (839 vs. 851)
▪ No difference in hospitalization for CHF
● Reduced doses should be given to patients with
renal insufficiency
● Avoid these agents in patients with pancreatic
disease or with other significant risk factors for acute
pancreatitis (heavy alcohol use, severely elevated
serum triglycerides, hypercalcemia)
GLP-1 Agonists
● Insulin secretagogues: agents that enhance GLP-1
receptor signaling
● MOA: activates GLP-1 receptors in pancreatic B-cell
and nervous system
● Increases glucose-induced insulin secretion,
decreases glucagon, decreases gastric emptying,
increases satiety
● May increase B-cell mass
● May cause mild weight loss and appetite
suppression
● CV effects: decreases weight and visceral fat,
decreases BP, increases urinary sodium, improved
endothelial function, decrease triglycerides and free
fatty acid levels
● Several GLP-1 agonists drugs differing in duration of
action
o Exenatide (Byetta): short-acting, BID, need renal
adjustment
o Exenatide (Bydurean): long-acting, weekly, need
renal adjustment
o Lixisenatide (Lyxumia): intermediate-acting,
daily
o Liraglutide (Victoza): long-acting, weekly
o Short-acting: exanatide and lixisenatide
▪ Provide mostly postprandial coverage
o Long-acting: liraglutide, exenatide, albiglutide,
dulaglutide, and lixisenatide
▪ Reduce both the postprandial and fasting
glucose
● Disadvantages: causes nausea, vomiting, or
diarrhea; pancreatic risk; medullary thyroid cancer
● These drugs are very expensive
● Seldom used
Sodium glucose co-transporter 2 (SGLT-2) Inhibitors
● MOA: inhibits SGLT-2 which is expressed almost
exclusively in the proximal and convoluted tubule in
the kidney
● Inhibits glucose reabsorption in the proximal tubule
of the kidney, lowers the renal threshold for glucose,
and leads to increased urinary glucose excretion
● Glucose-lowering effect is insulin-dependent and not
related to changes in insulin sensitivity or secretion
● Also impair proximal reabsorption of sodium
o Their use is associated with diuretic effect and 3-
6 mmHg reduction in systolic BP
● Examples: canagliflozin (Invokana), dapagliflozin
(Forxiga), empagliflozin (Jardiance)
● Urine glucose: 60-100 mg/day
● A1c reduction of 0.8-1.0%
● Avoided if the patient has renal dysfunction
● CV effects:
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 Medicine 2 (Endocrinology) I Lecture #6A
DIABETES MELLITUS
Dr. S. Sible | October 6, 2021
o Vascular volume decreases the BP by 4-6
mmHg by inhibiting salt reabsorption in the
proximal tubule
o Weight reduction of 2.5-3.0 kg over 6-12 months
persisting for 2 years
o Small increase in LDL and HDL cholesterol
o Due to uric acid and glucose co-transport in the
proximal tubule, it decreases also the serum uric
acid
o Meta-analyses suggest decreased CV risk
● Advantages:
o No hypoglycemia of hypoglycemia is unusual
o Unique action: can be combined with other
antidiabetic agents
o CV events appear beneficial
● Disadvantages:
o Due to increased urinary glucose, urinary and
genital mycotic infections are more common in
both men and women
o UTIs
o Vulvovaginitis, balanitis
o Osmotic diuresis causing possible dehydration
and hypotension
o Increase hepatic glucose output
o Risk of diabetic ketoacidosis
▪ Inhibition of SGLT2 on the alpha cell may
lead to increased glucagon and
consequently liver production of glucose and
ketones
▪ May not be recognized as glucose because
the glucose may not be as high as those
typically seen in DKA
▪ Mechanism not unresolved, there are
several hypotheses
▪ Increase in glucagon, decrease in insulin
▪ Increased absorption of ketone with delayed
clearance of ketone (may not see ketonuria)
▪ Associated dehydration, fluid loss or poor
fluid intake (vomiting) and infections, in a
poor metabolic milieu, might also trigger this
event, making the patient ketosis-prone
● These agents should not be prescribed for patients
with Type 1 DM or pancreatogenic forms of DM
associated with insulin deficiency
Insulin
● Administration of basal insulin is essential in
individuals with Type 1 DM for regulating glycogen
breakdown, gluconeogenesis, lipolysis, and
ketogenesis
● Insulin should be considered as part of the initial
therapy in Type 2 DM, particularly in
o Lean individuals or those with severe weight loss
o Individuals with underlying renal or hepatic
disease that precludes oral glucose-lowering
agents, or
o Individuals who are hospitalized or acutely ill
● Some physicians prefer a relatively low, fixed tarting
dose of long-acting insulin (5-15 units) or a weight-
based dose (may not be the best approach)
o Start with 10-20 units depending on A1c or 0.2
units/kg
● With lower A1c and relatively stable glucose, control
may require only basal insulin
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● Can often start with a low dose, but very large
amounts may eventually be needed due to
resistance requiring vigorous titration
● May need large amounts in sick patients due to
stress, steroids, tube feeds, etc.
● Severely insulin-deficient: needs may approach like
that in Type 1 diabetes requiring basal/bolus regimen
or insulin pump therapy
● Other insulin formulations that have a combination of
short-acting and long-acting insulin are sometimes
used in patients with Type 2 DM because of
convenience but
o Do not allow independent adjustment
o Do not achieve the same degree of glycemic
control as basal/bolus regime
● In selected patients with Type 2 DM, insulin-infusion
devices may be considered
See Appendix B-D for the list of other agents used for
treatment of Type 1 or Type 2 diabetes and for the list
of different insulin preparations
END OF TRANSCRIPTION
REFERENCES
• Harrison’s Principles of Internal Medicine, 20th ed.,
(Vol. 1 & Vol.2) Chapter 396-397
• Dr. Sible’s PPT and audio recording
• https://www.who.int/images/default-
source/departments/ncds/diabetes/whd2016-
diabetes-infographic-v2-page-
1.png?sfvrsn=a5638d91_2
• IDF Diabetes Atlas, the International Diabetes
Federation, 2017
ABBREVIATIONS
ADA – American Diabetes Association
BMI – Body Mass Index
CAD – Coronary Artery Disease
CHF – Congestive Heart Failure
CVD – Cardiovascular Disease
DCCT – Diabetes Control and Complications Trial
DM – Diabetes Mellitus
FBS – Fasting blood sugar or Fasting blood glucose
GDM – Gestational Diabetes Mellitus
GFR – Glomerular Filtration Rate
GLP – Glucagon-like Peptide
HbA1c – Hemoglobin A1c
HC – Hip Circumference
IDF – International Diabetes Federation
IFG – Impaired Fasting Glucose
IGT – Impaired Glucose Intolerance
IMT – Intima Medial Thickness
MI – Myocardial Infarction
MODY – Maturity-Onset Diabetes of the Young
OGTT – Oral Glucose Tolerance Test
PAD – Peripheral Arterial Disease
RBS – Random Blood Sugar or Random Blood Glucose
UKPDS – United Kingdom Prospective Diabetes Study
WC – Waist Circumference
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Dr. S. Sible | October 6, 2021

APPENDIX

Appendix A. Nutritional Recommendations for Adults with Diabetes or Prediabetes

Appendix B. Drugs for type 2 diabetes beyond metformin (less often used)
Drug Actions Mechanism Advantages Disadvantages
Meglitinides,
↑ β-cell insulin Action focused on Not very effective; other concerns
repaglinide, Potassium channels
secretion time of food intake shared with sulfonylureas
nateglinide
Thiazolidine-diones ↑ insulin Pioglitazone: Any use is questionable; weight
(TZDs): sensitivity ↑ HDL, gain, edema, CHF, ↑ LDL, bone
Activate PPAR-y
pioglitazone, mainly in ↓ triglycerides, fractures, bladder CA
rosiglitazone muscle no hypoglycemia Rosiglitazone: ↑ CV effects
α-glucosidase ↓ intestinal
Non-systemic,
inhibitors: glucose Inhibit α-glucosidase Not very effective, GI gas, diarrhea
no hypoglycemia
acarbase, miglitol absorption
Bile acid Constipation, ↑ triglycerides,
Colesevelam Unclear No hypoglycemia
sequestrant ↓ absorption of meds
↑ insulin Hypothalamic Dizziness, syncope, nausea,
Bromocriptine No hypoglycemia
sensitivity dopaminergic effect fatigue, rhinitis, long term safety (?)

Appendix C. Properties of Insulin Preparations

Preparation Onset (hours) Peak (hours) Duration (hours) Appearance
Short-acting
Regular 0.5 – 1 2–4 5–8 Clear
Lispro 0.25 0.5 – 1.5 3–5 Clear
Aspart 0.25 1–3 3–5 Clear
Glulisine 0.25 – 0.5 0.5 – 1 4 Clear
Inhaled human insulin 0.5 – 1 2–3 3
Long-acting
NPH 1–2 4 – 10 14 Cloudy
Detemir 3–4 6–8 20 – 24 Clear
Glargine 1.5 flat 24 Clear
Degludec 1–9 - 42
Combinations
Classic 70/30 0.5 – 1 3–6 14 Cloudy
Aspart mix 70/30 0.1 – 0.2 1–4 18 – 24 Cloudy
Lispro mix 75/25 0.25 – 0.5 0.5 – 2.5 14 – 24 Cloudy
Lispro mix 50/50 0.25 – 0.5 0.5 – 3 14 – 24 Cloudy

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 Medicine 2 (Endocrinology) I Lecture #6A
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Dr. S. Sible | October 6, 2021

Appendix D. Agents used for treatment of type 1 or type 2 diabetes

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