TYPE 2 DIABETES MELLITUS
EPIDEMIOLOGY, RISK FACTORS
AND PATHOGENESIS
TYPE 2 DIABETES MELLITUS
• heterogeneous group of disorders
characterized by variable degrees of insulin
resistance, impaired insulin secretion, and
increased hepatic glucose production
• Predominantly insulin resistance with relative
insulin deficiency to a predominant insulin
secretory defect with insulin resistance
EPIDEMIOLOGY
• 30 million cases in 1985 to 463 million in 2019
• 642 million individuals will have diabetes by the
year 2040
• the prevalence of type 2 DM is rising much more
rapidly, presumably because of dietary changes
and increasing obesity, reduced activity levels
as countries become more industrialized, and
aging of the population.
Highest in certain Pacific islands and the Middle East and
intermediate in countries such as India and the United States.
genetic, behavioral, and environmental factors
• In Asia, the prevalence of diabetes is increasing rapidly, with an
onset at a lower body mass index (BMI) and younger age,
greater visceral adiposity, and reduced insulin secretory
capacity.
• major cause of mortality.
• seventh leading cause of death
• In 2019, data from the IDF suggest that diabetes was
responsible for nearly 4.2 million deaths worldwide, accounting
for 11.3% of global all-cause mortality in adults aged 20-79
years.
(1)a large number of individuals who meet the current criteria for DM
are asymptomatic and unaware that they have the disorder
(2) (2) epidemiologic studies suggest that type 2 DM may be present
for up to a decade before diagnosis
(3)(3) some individuals with type 2 DM have one or more diabetes-
specific complications at the time of their diagnosis
(4) (4) treatment of type 2 DM may favorably alter the natural history
of DM
(5)(5) diagnosis of prediabetes should spur efforts for diabetes
prevention.
(6)The ADA recommends screening all individuals aged >45 years
every 3 years and screening individuals at an earlier age if they
are overweight (BMI >25 kg/m2 or ethnically relevant definition for
overweight) and have one additional risk factor for diabetes
• Glucose homeostasis reflects a balance between
energy intake from ingested food, hepatic glucose
production (gluconeogenesis), and peripheral
tissue glucose uptake and utilization. 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
PATHOPHYSIOLOGY
• Insulin resistance and abnormal insulin secretion are central to the development
of type 2 DM.
• insulin resistance precedes an insulin secretory defect but that diabetes
develops only when insulin secretion becomes inadequate.
• Type 2 DM likely encompasses a range of disorders with the common phenotype
of hyperglycemia.
• Type 2 DM has a strong genetic component.
• The concordance of type 2 DM in identical twins is between 70% and 90%.
Individuals with a parent with type 2 DM have an increased risk of diabetes; if
both parents have type 2 DM, the risk approaches 70%. Insulin resistance, as
demonstrated by reduced glucose utilization in skeletal muscle, is present in
many nondiabetic, first degree relatives of individuals with type 2 DM.
• The disease is polygenic and multifactorial, because in addition to genetic
susceptibility, environmental factors (such as obesity, poor nutrition, and
physical inactivity) modulate the phenotype.
• Shared environmental and lifestyle factors also contribute to the high
concordance in families
• Type 2 DM is characterized by impaired insulin secretion, insulin
resistance, excessive hepatic glucose production, abnormal fat
metabolism, and systemic low-grade inflammation
• As insulin resistance and compensatory hyperinsulinemia progress,
the pancreatic islets in certain individuals are unable to sustain the
hyperinsulinemic state, manifesting as IGT, defined as elevations in
postprandial glucose.
• A decline in insulin secretion and/or increased glucagon secretion
causes an increase in hepatic glucose production leading to fasting
hyperglycemia.
• Ultimately, frank beta cell failure ensues as a combination of these
mechanisms leading to the manifestation of type 2 diabetes
INSULIN RESISTANCE
• Insulin resistance, the decreased ability of insulin to act effectively on target
tissues (especially muscle, liver, and fat), is a prominent feature of type 2 DM and
results from a combination of genetic susceptibility, obesity, and metabolic
inflammation.
• In type 2 DM, both insulin potency and efficacy are reduced leading to an overall
decrease in glucose utilization under many conditions (30–60% lower than in
normal individuals).
• Insulin resistance impairs glucose utilization by insulin-sensitive tissues (skeletal
muscle) and in liver, coupled with elevated glucagon, leads to increased hepatic
glucose output.
• Increased hepatic glucose output predominantly accounts for increased FPG levels,
whereas decreased peripheral glucose utilization results in postprandial
hyperglycemia
IMPAIRED INSULIN SECRETION
• In type 2 DM, insulin secretion initially increases in response to insulin resistance
to maintain normal glucose tolerance.
• Initially, the insulin secretory defect is mild and selectively involves glucose-
stimulated insulin secretion, including a greatly reduced first secretory phase.
• The response to other nonglucose secretagogues, such as arginine, is preserved,
but overall beta cell function is reduced by as much as 50% at the onset of type
2 DM.
• Abnormalities in proinsulin processing are reflected by increased secretion of
proinsulin in type 2 DM. Eventually, the insulin secretory defect is progressive.
INCREASED HEPATIC GLUCOSE AND
LIPID PRODUCTION
• In type 2 DM, insulin resistance in the liver reflects the failure of hyperinsulinemia to
suppress gluconeogenesis, which results in fasting hyperglycemia and decreased
glycogen storage by the liver in the postprandial state.
• Increased hepatic glucose production occurs early in the course of diabetes, although
likely after the onset of insulin and glucagon secretory abnormalities and insulin
resistance in skeletal muscle.
• As a result of insulin resistance in adipose tissue, lipolysis and free fatty acid flux from
adipocytes are increased and efficiently cleared by liver leading to increased very-low-
density lipoprotein (VLDL)-triglyceride synthesis in hepatocytes and secretion from
liver.
• This is also responsible for the dyslipidemia found in type 2 DM (elevated
triglycerides, reduced high-density lipoprotein [HDL], and increased small dense low-
density lipoprotein [LDL] particles).
EVALUATION
HISTORY
• current weight, any recent changes in weight, family history of DM and its
complications, sleep history, risk factors for cardiovascular disease, exercise,
smoking status, history of pancreatic disease, and ethanol use. Symptoms of
hyperglycemia include polyuria, polydipsia, weight loss, fatigue, weakness, blurry
vision, frequent superficial infections (vaginitis, fungal skin infections), and slow
healing of skin lesions after minor trauma.
• Metabolic derangements relate mostly to hyperglycemia and to the catabolic state
of the patient
• Blurred vision results from changes in the water content of the lens and resolves as
hyperglycemia is controlled.
• In addition, the presence of DM-related comorbidities should be established
cardiovascular disease, hypertension, dyslipidemia
EXAMINATION
• weight and BMI, retinal examination, orthostatic blood pressure, foot examination, peripheral
pulses, and insulin injection sites.
• Depending on other risk factors, a blood pressure >130/80 mmHg or >140/90 mmHg is
considered hypertension in individuals with diabetes.
• Because periodontal disease is more frequent in DM, the teeth and gums should also be
examined.
• An annual foot examination should
• (1) assess blood flow (pedal pulses), sensation (vibratory sensation [128-MHz tuning fork at the
base of the great toe], the ability to sense touch with a monofilament [5.07, 10-g monofilament]),
pinprick sensation, ankle reflexes, and nail care;
• (2) look for the presence of foot deformities such as hammer or claw toes and Charcot foot; and
• (3) identify sites of potential ulceration. The ADA recommends annual screening for distal
symmetric polyneuropathy beginning with the initial diagnosis of diabetes and annual screening
for autonomic neuropathy 5 years after diagnosis of type 1 DM and at the time of diagnosis of
type 2 DM. This testing is aimed at detecting loss of protective sensation (LOPS) caused by
diabetic neuropathy
Type 1 DM
Type 2 DM
(1) lean body habitus;
(1)obesity; 80% are obese, but
(2) requirement of insulin
elderly individuals may be
as the initial therapy;
lean;
(3) propensity to develop
(2) may not require insulin
ketoacidosis
therapy initially
(4) a family or personal
(3) may have associated
history of other
conditions such as insulin
autoimmune disorders such
resistance, hypertension,
as autoimmune thyroid
cardiovascular disease,
disease, adrenal
dyslipidemia, or polycystic
insufficiency, pernicious
ovarian syndrome.
anemia, celiac disease, and
vitiligo.
LABORATORY ASSESSMENT
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