1. Diabetes mellitus - pathogenesis, clinical features.
De nition: Diabetes mellitus (DM) describes a group of metabolic diseases that are characterized
by chronic hyperglycemia (elevated blood glucose levels). The two most common forms are type
1 and type 2 diabetes mellitus. Type 1 is the result of an autoimmune response that triggers the
destruction of insulin-producing β cells in the pancreas and results in an absolute insulin
de ciency. Type 2, which is much more common, has a strong genetic component as well as a
signi cant association with obesity and sedentary lifestyles. Type 2 diabetes is characterized by
insulin resistance (insu cient response of peripheral cells to insulin) and pancreatic β cell
dysfunction (impaired insulin secretion), resulting in relative insulin de ciency. This form of
diabetes usually remains clinically inapparent for many years. However, abnormal metabolism
(prediabetic state or impaired glucose intolerance), which is associated with chronic
hyperglycemia, causes microvascular and macrovascular changes that eventually result in
cardiovascular, renal, retinal, and neurological complications. In addition, type 2 diabetic patients
often present with other conditions (e.g. hypertension, dyslipidemia, obesity) that increase the risk
of cardiovascular disease (e.g., myocardial infarction). Renal insu ciency is primarily responsible
for the reduced life expectancy of patients with DM.
Etiology:
- Type 1
- Autoimmune β cell destruction in genetically susceptible individuals
- HLA association. HLA-DR3 and HLA-DR4 positive patients are 4–6 times more likely to
develop type 1 diabetes.
- Association with other autoimmune conditions
- Hashimoto thyroiditis
- Type A gastritis
- Celiac disease
- Primary adrenal insu ciency
- Type 2
- Hereditary and environmental factors
- Association with metabolic syndrome
- Risk factors
- Obesity, high-calorie diet
- High waist-to-hip ratio (visceral fat accumulation)
- Physical inactivity
- First-degree relative with diabetes
- Ethnicity
- Hypertension
- Dyslipidemia
- History of gestational diabetes
Classi cation:
- Type 1: formerly known as insulin-dependent (IDDM) or juvenile-onset diabetes mellitus
- Autoimmune (type 1A)
- Idiopathic (type 1B)
- Type 2: formerly known as non-insulin-dependent (NIDDM) or adult-onset diabetes mellitus
- Other types of diabetes mellitus
- Genetic defects in the β cell function: MODY (maturity onset diabetes of the young)
- Di erent forms of autosomal dominant inherited diabetes mellitus that manifest before the
age of 25 years and are not associated with obesity or autoantibodies
- 6 subtypes, the most common being MODY II and MODY III
- Caused by genetic defects in the glucokinase gene and hepatocyte nuclear factor-1-α,
respectively
- In contrast to all other subtypes, MODY II is not associated with an increased risk of
microvascular disease and can be managed with diet alone, despite stable hyperglycemia
and chronically elevated HbA1C levels
- All other subtypes require medical treatment, either with insulin or sulfonylureas
- Genetic defects in insulin function
- Diseases of the exocrine pancreas (pancreoprivic diabetes mellitus)
- Endocrinopathies: Cushing disease, acromegaly
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, - Drug-induced diabetes: e.g., corticosteroids
- Infections: e.g., congenital rubella infection
- Rare immunological diseases: sti person syndrome
- Gestational diabetes
Pathophysiology:
- type 1
- Genetic susceptibility
- Environmental trigger (often associated with previous viral infection)
- → Autoimmune response with production of autoantibodies, e.g., Anti-glutamic acid
decarboxylase antibody (Anti-GAD), that target insulin-producing cells → progressive
destruction of insulin-producing β cells in the pancreatic islets by autoreactive T cells →
destruction of 80–90% of β cells
- → Absolute insulin de ciency → elevated blood glucose levels
- type 2
- Two major mechanisms:
- Peripheral insulin resistance
- Numerous genetic and environmental factors
- Central obesity → increased plasma levels of free fatty acids → impaired insulin-
dependent glucose uptake into hepatocytes, myocytes, and adipocytes
- Increased serine kinase activity in liver, fat and skeletal muscle cells →
phosphorylation of insulin receptor substrate (IRS)-1 → decreased a nity of IRS-1 for
PI3K → decreased expression of GLUT4 channels → decreased cellular glucose
uptake
- Pancreatic β cell dysfunction
- Accumulation of pro-amylin (islet amyloid polypeptide) in the pancreas → decreased
endogenous insulin production
- Initially, insulin resistance is compensated by increased insulin and amylin secretion.
- Over the course of the disease, insulin resistance progresses, while insulin secretion capacity
declines.
- After a period of impaired glucose tolerance with isolated postprandial hyperglycemia,
diabetes manifests with fasting hyperglycemia.
Clinical features:
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, Diabetes mellitus should be suspected in patients with recurrent cellulitis, candidiasis,
dermatophyte infections, gangrene, pneumonia (particularly TB reactivation), in uenza,
genitourinary infections (UTIs), osteomyelitis, and/or vascular dementia
Diagnostics:
- additional tests
- Speci c autoantibodies for diabetes mellitus type 1
- Anti-GAD antibodies
- Anti-tyrosine phosphatase-related islet antigen (IA-2)
- Islet cell surface antibody (ICSA; against ganglioside)
- C-peptide
- ↓ C-peptide levels indicate an absolute insulin de ciency → type 1 diabetes
- ↑ C-peptide levels may indicate insulin resistance and hyperinsulinemia → type 2 diabetes
- Urine analysis
- Microalbuminuria: an early sign of diabetic nephropathy
- Glucosuria: Testing urine for glucose does not su ce to establish the diagnosis of
diabetes mellitus.
- Ketone bodies (usually accompanied by glucosuria): positive in acute metabolic
decompensation in diabetes mellitus (diabetic ketoacidosis)
DD:
Other: glucaginoma, somatostatinoma
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, 2. Diabetes mellitus - treatment with insulin and oral medications.
Treatment:
Antihyperglycemic therapy algorithm for type 2 DM
- HbA1C target for adults: < 7% (53 mmol/mol)
- The guidelines for the treatment of DM recommend an individualized treatment strategy.
- If the target A1C is not reached within 3 months with conservative measures (e.g., diet,
exercise), the next step in the therapeutic algorithm should be initiated.
De nition: Diabetes mellitus (DM) describes a group of metabolic diseases that are characterized
by chronic hyperglycemia (elevated blood glucose levels). The two most common forms are type
1 and type 2 diabetes mellitus. Type 1 is the result of an autoimmune response that triggers the
destruction of insulin-producing β cells in the pancreas and results in an absolute insulin
de ciency. Type 2, which is much more common, has a strong genetic component as well as a
signi cant association with obesity and sedentary lifestyles. Type 2 diabetes is characterized by
insulin resistance (insu cient response of peripheral cells to insulin) and pancreatic β cell
dysfunction (impaired insulin secretion), resulting in relative insulin de ciency. This form of
diabetes usually remains clinically inapparent for many years. However, abnormal metabolism
(prediabetic state or impaired glucose intolerance), which is associated with chronic
hyperglycemia, causes microvascular and macrovascular changes that eventually result in
cardiovascular, renal, retinal, and neurological complications. In addition, type 2 diabetic patients
often present with other conditions (e.g. hypertension, dyslipidemia, obesity) that increase the risk
of cardiovascular disease (e.g., myocardial infarction). Renal insu ciency is primarily responsible
for the reduced life expectancy of patients with DM.
Etiology:
- Type 1
- Autoimmune β cell destruction in genetically susceptible individuals
- HLA association. HLA-DR3 and HLA-DR4 positive patients are 4–6 times more likely to
develop type 1 diabetes.
- Association with other autoimmune conditions
- Hashimoto thyroiditis
- Type A gastritis
- Celiac disease
- Primary adrenal insu ciency
- Type 2
- Hereditary and environmental factors
- Association with metabolic syndrome
- Risk factors
- Obesity, high-calorie diet
- High waist-to-hip ratio (visceral fat accumulation)
- Physical inactivity
- First-degree relative with diabetes
- Ethnicity
- Hypertension
- Dyslipidemia
- History of gestational diabetes
Classi cation:
- Type 1: formerly known as insulin-dependent (IDDM) or juvenile-onset diabetes mellitus
- Autoimmune (type 1A)
- Idiopathic (type 1B)
- Type 2: formerly known as non-insulin-dependent (NIDDM) or adult-onset diabetes mellitus
- Other types of diabetes mellitus
- Genetic defects in the β cell function: MODY (maturity onset diabetes of the young)
- Di erent forms of autosomal dominant inherited diabetes mellitus that manifest before the
age of 25 years and are not associated with obesity or autoantibodies
- 6 subtypes, the most common being MODY II and MODY III
- Caused by genetic defects in the glucokinase gene and hepatocyte nuclear factor-1-α,
respectively
- In contrast to all other subtypes, MODY II is not associated with an increased risk of
microvascular disease and can be managed with diet alone, despite stable hyperglycemia
and chronically elevated HbA1C levels
- All other subtypes require medical treatment, either with insulin or sulfonylureas
- Genetic defects in insulin function
- Diseases of the exocrine pancreas (pancreoprivic diabetes mellitus)
- Endocrinopathies: Cushing disease, acromegaly
fffifi fi fi ffi ffi ffi fi
, - Drug-induced diabetes: e.g., corticosteroids
- Infections: e.g., congenital rubella infection
- Rare immunological diseases: sti person syndrome
- Gestational diabetes
Pathophysiology:
- type 1
- Genetic susceptibility
- Environmental trigger (often associated with previous viral infection)
- → Autoimmune response with production of autoantibodies, e.g., Anti-glutamic acid
decarboxylase antibody (Anti-GAD), that target insulin-producing cells → progressive
destruction of insulin-producing β cells in the pancreatic islets by autoreactive T cells →
destruction of 80–90% of β cells
- → Absolute insulin de ciency → elevated blood glucose levels
- type 2
- Two major mechanisms:
- Peripheral insulin resistance
- Numerous genetic and environmental factors
- Central obesity → increased plasma levels of free fatty acids → impaired insulin-
dependent glucose uptake into hepatocytes, myocytes, and adipocytes
- Increased serine kinase activity in liver, fat and skeletal muscle cells →
phosphorylation of insulin receptor substrate (IRS)-1 → decreased a nity of IRS-1 for
PI3K → decreased expression of GLUT4 channels → decreased cellular glucose
uptake
- Pancreatic β cell dysfunction
- Accumulation of pro-amylin (islet amyloid polypeptide) in the pancreas → decreased
endogenous insulin production
- Initially, insulin resistance is compensated by increased insulin and amylin secretion.
- Over the course of the disease, insulin resistance progresses, while insulin secretion capacity
declines.
- After a period of impaired glucose tolerance with isolated postprandial hyperglycemia,
diabetes manifests with fasting hyperglycemia.
Clinical features:
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, Diabetes mellitus should be suspected in patients with recurrent cellulitis, candidiasis,
dermatophyte infections, gangrene, pneumonia (particularly TB reactivation), in uenza,
genitourinary infections (UTIs), osteomyelitis, and/or vascular dementia
Diagnostics:
- additional tests
- Speci c autoantibodies for diabetes mellitus type 1
- Anti-GAD antibodies
- Anti-tyrosine phosphatase-related islet antigen (IA-2)
- Islet cell surface antibody (ICSA; against ganglioside)
- C-peptide
- ↓ C-peptide levels indicate an absolute insulin de ciency → type 1 diabetes
- ↑ C-peptide levels may indicate insulin resistance and hyperinsulinemia → type 2 diabetes
- Urine analysis
- Microalbuminuria: an early sign of diabetic nephropathy
- Glucosuria: Testing urine for glucose does not su ce to establish the diagnosis of
diabetes mellitus.
- Ketone bodies (usually accompanied by glucosuria): positive in acute metabolic
decompensation in diabetes mellitus (diabetic ketoacidosis)
DD:
Other: glucaginoma, somatostatinoma
fi ffi
fi fl
, 2. Diabetes mellitus - treatment with insulin and oral medications.
Treatment:
Antihyperglycemic therapy algorithm for type 2 DM
- HbA1C target for adults: < 7% (53 mmol/mol)
- The guidelines for the treatment of DM recommend an individualized treatment strategy.
- If the target A1C is not reached within 3 months with conservative measures (e.g., diet,
exercise), the next step in the therapeutic algorithm should be initiated.
