Diabetes mellitus, type 2E11.90

Synonyms

Sugar disease; diabetes; urinary dysfunction; sugar urine dysfunction; honey urine dysfunction;

First Describer

As early as 1,500 B.C., writings describing "excessive voiding of the urine" were found in Egypt. Indian physicians later described urine as honey-sweet because it attracted ants.

The Indian surgeon Sushruta differentiated two different types of the disease around 400 - 500 CE, which were later called type 1 and type 2.

The word "diabetes" (Greek "siphon") was coined by Aretaeus in 100 CE.

The term "mellitus" (Latin: sweet as honey) was coined in 1798 by the British Surgeon General John Rollo to distinguish diabetes from diabetes insipidus.

In 1869, Paul Langerhans identified cells that were later named after him as "Langerhans' islets" or "Langerhans' cells".

Mering and Minkowski discovered in 1889 that removal of the pancreas in dogs led to diabetes.

De Mayer and Schaefer coined the name "insulin" for the secretions of the islets of Langerhans (insula) in the pancreas in 1909 and 1910, respectively.

In 1921, Banting, Best, and Collip ligated the pancreatic duct in the laboratory, destroying the exocrine pancreas but leaving the islet cells intact.

The advocacy of diet and exercise in type 2 DM was introduced in the 19th century by Joslin and Fitz.

It was not until 1922 that Leonhard Thompson made the decisive breakthrough regarding the treatment of DM with a bovine insulin extract.

The first oral antidiabetic drugs were developed in the 1950s. The needle-free administration of insulin was achieved by Derata in 1979, and a year later, in 1980, the first human insulin was produced by Graham Bell.

(Lakhtakia 2013)

Type 2 diabetes mellitus (DM) is a metabolic disorder that exhibit the phenotype of hyperglycemia (Kasper 2015).

DM is divided into 2 major groups based on the pathogenic process leading to the hyperglycemia:

• Type 1 DM
• type 2 DM

In addition, there are also less frequent groups:

• Pregnancy diabetes
• genetic defects of beta-cell development or function
• Genetic defects of the insulin effect such as leprechaunism, lipodystrophy syndromes, etc.
• other genetic syndromes
• Diseases of the exogenous pancreas such as pancreatitis, carcinoma, hemochromatosis, etc.
• Endocrinopathies such as Cushing's syndrome, acromegaly, hyperthyroidism, pheochromocytoma, etc.
• Certain drugs such as glucocorticoids, thiazides, antipsychotics, hydantoins etc.
• Infections such as congenital rubella, coxsackievirus, cytomegaly etc.
• Unusual forms of immune-mediated diabetes such as anti-insulin receptor antibodies, stiff person syndrome etc.

(Kasper 2015)

Type 2 DM occurs worldwide (Herold 2020). A total of approx. 422 million people suffer from DM (Diederich 2020). The number of unreported cases is between 35 % and 40 % (Herold 2020).

The prevalence is increasing and dependent on age. Thus, at < 50 years of age, only 2% - 3% become ill, at > 60 years of age about 15% and at > 70 years of age up to 22% of the population.

By the age of 70, more men than women are affected (prevalence is 8.4% in men and 6.4% in women [Diederich 2020]). Educational status also appears to play a role (Herold 2020).

The genetic component plays a major role in type 2 DM. The concordance in identical twins, for example, is between 70 % - 90 %, and if both parents have type 2 DM, the risk of also developing the disease is 40 % (Kasper 2015).

Etiologically, four factors play a central role in type 2 DM in varying degrees of severity:

• 1. insulin resistance
• 2. insulin secretion

It is disturbed by a defect of the beta and alpha cells (hyperglucagonism)

• 3. progressive apoptosis of beta cells
• 4. Decreased secretion and action of incretin.

(Herold 2020)

In most studies, it is believed that insulin resistance precedes the defect in insulin secretion. However, DM only develops when insulin secretion is no longer adequate (Kasper 2015). In a Swedish study group on a cohort of 8,980 patients, the proportion of reduced insulin secretion at initial diagnosis was approximately 17.5% (Bahrmann 2018).

Risk factors of type 2 DM disease include:

• DM in the family in parents or siblings
• already diagnosed elevated fasting blood glucose (impaired fasting glucose = IFG)
• impaired glucose tolerance (IGT)
• haemoglobin A1c of 5.7 - 6.4
• Obesity (BMI ≥ 25 kg / m²; approx. 80 % are at least overweight [Herold 2020])
• anamnestic gestational diabetes
• birth of a child of > 4 kg
• Polycystic ovary syndrome (PCO or PCOS)
• acanthosis nigricans
• physical inactivity
• arterial hypertension with values ≥ 140 / 90 mmHg
• HDL cholesterol < 35 mg / dl
• triglycerides > 250 mg / dl
• ethnicity (e.g., Latino, Pacific Islander, African American, Asian American).

(Kasper 2015)

• Steatosis hepatis
• Syndromal disorders such as:
  • Trisomy 21
  • Turner syndrome

(Diederich 2020)

In type 2 DM, as a result of the defect in the beta cells, the first insulin secretion that occurs in healthy individuals, which takes place approx. 5 - 10 min after a meal, is missing. This leads to increased postprandial glucose levels and consequently to increased insulin secretion, the so-called postprandial hyperinsulinemia. This further increases endogenous insulin resistance and leads to a vicious circle with functional failure of the beta cells (Schatz 2006).

The pathophysiology depends on the ethnic group.

In Africans, Asians and Latin Americans, the pathophysiological processes have not yet been fully clarified. What is certain so far is increased insulin resistance in Latin Americans, greater beta cell dysfunction in Asians, who also develop the disease at a younger age and with a lower BMI (Kasper 2015).

In Europeans, we find:

• Impaired insulin secretion:

The early phase of the normally biparietal postprandial secretion of insulin is disturbed, causing postprandial hyperglycemia [Herold 2020]).

• Onset of insulin resistance:

Caused by a disturbance in signal transduction due to a pre-receptor defect, a receptor defect with down-regulation (i.e., sensitivity and density of insulin receptors are decreased), and a post-receptor defect (Herold 2020).

• Excessive hepatic glucose production (also exacerbates hyperglycemia [Herold 2020]).
• an apoptosis of the islet cells:

Hyperglycemia does not occur until > 50% of islet cells are apoptic (Herold 2020).

• incretin secretion and action are reduced (Herold 2020)
• there is an abnormal lipid metabolism:

Type 2 DM develops in the majority of cases from a metabolic syndrome

(Herold 2020).

At the onset of type 2 disease, glucose tolerance remains almost normal despite pre-existing insulin resistance, as pancreatic beta cells are able to compensate by increasing insulin secretion.

In later stages, the hyperinsulinemic state can no longer be maintained and IGT characterized by elevation of postprandial glucose develops. Due to a decrease in insulin secretion and an increase in hepatic glucose production, an elevated fasting blood glucose occurs and ultimately beta cell failure (Kasper 2015).

The predominant age of manifestation for type 2 DM is usually > 40 years (Herold 2020).

Asians develop the disease at a younger age and with a lower BMI than Europeans (Kasper 2015).

Type 2 DM manifests insidiously and is often not even noticed by the patient himself (Herold 2020).

Symptoms tend to be non-specific such as:

• Fatigue
• Reduced performance
• Hyperglycemia-related symptoms such as:
  • Polyuria
  • polydipsia
  • nocturnal calf cramps due to disturbances in the electrolyte balance
  • visual disturbances due to a changing turgor of the eye lens
  • Weight loss (usually not as pronounced as in type 1 DM [Diederich 2020])
• Skin changes:
  • Pruritus (preferably in the genito-anal region)
  • recurrent skin infections caused by bacteria or mycosis, e.g. furunculosis, candidamycosis
  • rubeosis diabeticorum
• necrobiosis lipoidica
• Potency disorders
• Amenorrhea

(Herold 2020)

• Susceptibility to infections
• Cravings

(Diederich 2020)

The criteria for the diagnosis of DM are according to WHO:

• Fasting plasma blood glucose ≥ 126 mg / dl (7.0 mmol / l).
• Random- plasma- glucose ≥ 200 mg / dl (11.1 mmol / l)
• HbA1c ≥ 6.5% (48 mmol / mol)

(Bahrmann 2018)

The initial diagnosis of type 2 DM includes, in addition to a detailed medical history including family history, primarily laboratory chemistry tests (see "Laboratory").

In addition, screening for other risk factors should always be performed (Herold 2020).

Diseases associated with type 2 diabetes are:

• arterial hypertension
• obesity
• dyslipidemia
• Cardiovascular diseases (Kasper 2015).

Risk factors for cardiovascular disease are:

• biological age
• male sex > female sex
• diet
• Physical inactivity
• Lifestyle
• smoking status
• familial disposition
• genetic disposition
• duration of diabetes
• obesity
• dyslipidemia
• arterial hypertension
• subclinical arteriosclerosis
• left ventricular hypertrophy
• subclinical cardiovascular disease
• renal insufficiency
• albuminuria
• severe hypoglycemia
• severe metabolic instability

(Bahrmann 2018)

Abdominal sonography

Steatosis hepatis and hepatomegaly are often found (Diederich 2020).

The kidneys may appear reduced in size with a narrowed parenchymal border. The vessels may show arteriosclerotic changes (Herold 2020).

Vascular sonography

The neck vessels, abdominal aorta, iliac vessels and, if necessary, the leg arteries should be examined. A malignancy, especially a pancreatic Ca as a possible cause of sudden onset type 2 DM should be considered during the examination (Diederich 2020).

• blood glucose determination according to the hexokinase intermediate enzyme method. The criteria of the American Diabetes Association and the German Diabetes Society are:
  • venous fasting plasma glucose ≥ 126 mg / dl or ≥ 7.0 mmol / l
  • Occasional blood glucose ≥ 200 mg / dl or ≥ 11.1 mmol / l plus typical diabetes symptoms
  • oral glucose stress test ≥ 200 mg / dl or ≥ 11.1 mmol / l
• Glucose determination in urine:

This test has lost importance due to the simplicity of blood glucose measurement. From about 180 mg / dl glucose in the blood, the renal threshold for glucose is exceeded and glucosuria occurs. In pregnancy, however, this threshold is lower at < 150 mg / dl. The normal value for physiological glucosuria is up to 15 mg / dl. Test strips indicate glucosuria only from about 30 mg / dl (Herold 2020).

• Determination of ketone bodies:

The tendency to ketosis is only slight in type 2 DM (Paumgartner 2013).

• HbA1c- determination:

The HbA1c is considered a surrogate for metabolic control (Bahrmann 2018) and allows a statement on the BG- values of the last 6 - 8 weeks (Herold 2020).

Reference range:

< 5.7 % for non-diabetics

> 6.5 % for diabetics

The risk of suffering a myocardial infarction is increased by 40 % for values > 7 % and by 80 % for values > 8 %. The risk of suffering diabetic complications decreases by 20% for every 1% point decrease in each case (Herold 2020).

• False high concentrations can be measured at:
  • Hyperlipoproteinemia
  • in the 2nd half of pregnancy
  • during breastfeeding
  • chronic alcohol abuse
  • advanced renal insufficiency
• False low concentrations can be measured at:
  • after transfusions
  • in the first half of pregnancy
  • in the case of shortened erythrocyte life span as for example with
    • haemoglobinopathies
    • hemolytic anemia

(Herold 2020)

• Test for microalbuminuria:

1 x yearly at least in diabetics (Herold 2020).

• Determination of lipids:

Elevated at the onset of the disease:

• Plasma insulin
• C-peptide

(Herold 2020)

• Type 1 DM: In this case, in contrast to type 2 DM:
  • Ketonuria
  • Auto-antibodies GAD- Ak, IA2- Ak detectable
  • C-peptide clearly decreased
  • initial neuropathy not present
  • obesity rare
  • metabolic syndrome rare (Herrmann 2008)
  • absolute insulin deficiency
  • ketoacidosis (rarely occurring in type 2, as this is prevented by inhibition of lipolysis in adipose tissue (in contrast to type 1 DM), see also "Complications".
• Mitochondrial DM in combination with hearing loss or deafness (Diederich 2020).

Passenger hyperglycemia can occur in the setting:

• a myocardial infarction
• an apoplexy
• after treatment with thiazide saluretics
• acute poisoning (e.g. with CO)
• increased intracranial pressure
• Inflammation

(Herold 2020)

• Hyperglycemia:

Severe hyperglycemia is said to occur when blood glucose levels are > 300 mg / dl (> 16.7 mmol / l). Patients are not infrequently asymptomatic in hyperglycemia.

The dangers of hyperglycemia are:

- diabetic ketoacidosis (DK).

This is usually found exclusively in type 1 DM. However, it can also occur in type 2 diabetics of Hispanic or African American descent.

- Hyperosmolar hyperglycemic state (HHS)

This usually occurs in only patients with type 2 DM

(Kasper 2015)

• Hypoglycemia:

This can occur reactively postprandially after 2 - 5 h and also in the context of insulinotropic drug treatment such as treatment with sulfonylureas or insulin (Diederich 2020).

• Hyperosmolar coma:

This can occur with very high blood glucose levels of sometimes > 1,000 mg / dl and is associated with severe electrolyte imbalance as well as dehydration (Diederich 2020).

Chronic complications include:

• non-specific macroangiopathy such as:
  • coronary heart disease
  • myocardial infarction
  • arterial occlusive disease of the cerebral arteries
  • ischemic infarction
  • peripheral arterial occlusive disease
• diabetes-specific microangiopathy such as:
  • retinopathy due to local release of growth hormones (Diederich 2020)
  • microangiopathy of intramural coronary arteries (so-called small vessel disease)
  • Neuropathy
  • glomerulosclerosis (so-called Kimmelstiel-Wilson disease)
• diabetic nephropathy
• diabetic neuropathy
• diabetic cardiomyopathy
• diabetic retinopathy
• diabetic foot syndrome

(Herald 2020)

A milestone in the treatment of type 2 DM was the "UK Prospective Diabetes Study" (UKPDS), which was first published in 1998 at the European Diabetes Congress in Barcelona and covered a period of more than 20 years in more than 5,000 patients (Kellerer 2013).

The primary therapy goal is a permanent reduction of the HbA1c to values between 6.5 - 7.5 %. A value of < 6.5 % should only be aimed for in exceptional cases, provided that no serious side effects occur, in particular no hypoglycaemia and no massive weight loss (Diederich 2020).

However, in type 2 DM - in contrast to type 1 DM - not only glycemic control plays a role in treatment, but equally the treatment of concomitant diseases such as arterial hypertension, obesity, cardiovascular disease (CVD), dyslipidemia.

(Kasper 2015)

General measures in the form of a basic therapy:

• Change of diet:
  • 45 % - 60 % carbohydrates with a high fibre content
  • 15 % - 20 % protein (in the case of existing diabetic nephropathy, however, the protein content should be reduced to 0.8 EW / kg bw / d [Herold 2020])
  • 25 % - 30 % fat content
  • Reduction of animal saturated fatty acids
  • Increase in unsaturated vegetable fats
• Nutritional counselling (this should be individually adapted according to the guidelines of the German Diabetes Society)

(Diederich 2020)

• Several small meals (usually 5 / d)
• 2 - 3 x per week sea fish
• sweeteners allowed (in small amounts) include aspartame, cyclamate, saccharin and stevia
• fast absorbable monosaccharides and disaccharides should be avoided
• Alcohol only occasionally (women max. 10 g / d, men max. 20 g / d), as alcohol inhibits both gluconeogenesis in the liver and the early morning release of growth hormones such as STH [has a contrainsulin effect]. This increases the risk of hypoglycaemia.
• special dietary products are not necessary in DM

(Herold 2020)

• Change of exercise habits (especially important to increase insulin-independent glucose uptake and the sensitivity of the muscles to insulin)
• If necessary, physiotherapy or sports courses

(Diederich 2020)

• a BMI < 25 should be aimed for
• prophylaxis or therapy of possible complications
• In the case of premature arteriosclerosis, elimination of possible risk factors or appropriate therapeutic measures (Herold 2020).

If the target value of HbA1c of 6.5 % - 7.5 % cannot be achieved with the above-mentioned general measures (see "Therapy in general"), oral antidiabetics should also be used (Diederich 2020).

In the drug treatment of type 2 DM, there is a phase-appropriate step-by-step plan, the algorithm:

• 1st stage: Metformin is the drug of choice in overweight patients.
• Stage 2: Metformin plus GLP1 receptor antagonist (GLP1- AG) or low hypoglycaemic oral antidiabetic (OAD) plus - if necessary - a third low hypoglycaemic OAD / GLPA1- AG (see below).
• 3rd stage: OAD / insulin combination:
  • 3. a. OAD or GLPA1- AG plus basal insulin (in cases of progressive insulin resistance or relative depletion of endogenous insulin production)
  • 3. b. OAD plus basal insulin plus bolus insulin (in case of further depletion of insulin production)

(Herold 2020)

OAD:

Oral antidiabetic drugs include insulinotropic and non-insulinotropic drugs.

• Insulinotropic are:
  • Sulfonylureas
  • GLP1- RA
  • DPP4- inhibitors
  • Glinides

(Herold 2020)

• non-insulinotropic are:
  • Biguanides
  • Gliflozine (SGLT2 inhibitors)
  • Alpha-glucosidase inhibitors

(Herold 2020)

• high risk of hypoglycemiais present in:
  • Glinides
  • Sulfonylureas
  • Insulin
• low risk of hypoglycemiais with:
  • Biguanides
  • DPP4 inhibitors
  • alpha-glucosidase inhibitors
  • Gliflozine (SGLT2 inhibitors)
  • GLP1 RA

(Herold 2020)

• Increase in insulin secretion possible with e.g. sulfonylureas, DPP4 inhibitors
• Increase of insulin sensitivity can be achieved with e.g. glitazones, thiazolidine derivatives (Paumgartner 2013)
• Inhibition of the reabsorption of glucose by enhancing excretion in the urine by e.g. gliflozines (SGLT2 inhibitors [Jelinek 2021])
• Inhibition of hepatic gluconeogenesis such as by biguanides.

[Kasper 2015)

If the HbA1c- value at control is < 6.5 %, insulinotropic substances or insulin should be avoided because of the risk of hypoglycemia during treatment (Diederich 2020).

Newer medications such as glucosuria (SGLT 2- inhibitors) and incretin-based medications (GLP- 1- analogues) reduce the rate of cardiovascular disease and thus mortality.

Obesity can be treated adjuvantly by GLP- 1- analogue (such as liraglutide) (Diederich 2020).

Whole pancreas transplantation is exclusively a treatment option for type 1 DM (Kasper 2015).

In type 2 DM, bariatric surgery has shown promise. After surgery, many cases experienced a dramatic decrease in DM. In several large, non-blinded studies, surgery - compared to drug treatment - has been shown to be far more effective (Kasper 2015).

Gastric bypass is the most effective surgical method for permanent remission of type 2 DM. The duration of the DM disease determines the remission rates (Diederich 2020).

Type 2 DM is the seventh leading cause of death according to the WHO. In 2015, for example, approximately 1.6 million people died of type 2 DM (Diederich 2020).

The main cause of death in type 2 diabetes is cardiovascular disease (Kasper 2015). Myocardial infarction kills approximately 55% of diabetics (Herold 2020).

The lethality of hyperosmolar coma is about 15% higher than the lethality of ketoacidotic coma (Diederich 2020).

A type 2 DM is - according to a study in the Lancet 12 / 2017 - fully remissionable and therefore not incurable in manifest young diabetics by a very strict diet and regular physical exercise (Herold 2020).

With conservative therapy and pharmacological treatment, remission rates have been low to date. Bariatric surgery, on the other hand, has shown good success, so it can be assumed that this will probably play a greater role in treatment in the near future (Diederich 2020).

Prophylaxis

Since 2012, a screening examination, the so-called oral glucose tolerance test = oGTT, has been paid for by all statutory health insurers in Germany (Herold 2020).

In persons > 45 years with risk factors, the fasting BG should be measured every 3 years. This group includes individuals with:

• arterial hypertension, dyslipoproteinemia and obesity.
• family history or Find- Risk- Test positive
• persons of ethnic groups with a high risk of DM disease, e.g. Pima Indians
• history of gestational diabetes
• birth of a child of > 4.500 g
• anamnestic disturbed glucose homeostasis or pathological glucose tolerance

(Herold 2020)

Taxation of foods harmful to health is currently under political discussion (Diederich 2020).

Follow-up care

Aftercare concerns patients who have undergone bariatric surgery. Here, adjustments to the therapy of type 2 DM are often necessary in the course (Diederich 2020).

In patients with long-standing type 2 DM, regular checks are necessary even after remission, as secondary complications can progress despite currently good glucose values. In particular, the following examinations should be performed here:

• Ocular fundus
• renal function
• Vascular integrity
• Nerve function

(Diederich 2020)

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3. Herrmann F et al. (2008) Endocrinology for practice: diagnostics and therapy from A - Z. Georg Thieme Publishers Stuttgart / New York 35 - 45
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5. Jelinek A et al (2021) White series: pharmacology. Elsevier Urban and Fischer Publishers 190
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