Diabetes Mellitus Type 2: Causes

Pathogenesis (disease development)

The cells of the pancreas lie arranged in islands called islets of Langerhans. One type of cell in the islets of Langerhans is the β-cells (B cells). These cells produce insulin. Insulin is responsible for promoting the uptake of glucose from the blood. It also ensures the conversion of glucose into glycogen, which is an important storage form for glucose. In this form, glucose can be stored in the liver and our muscles without raising blood glucose levels. Thus, insulin ensures that blood glucose levels remain constant. Another type of cell is the α-cells (A-cells). They produce glucagon. This substance stimulates very specific enzymes to convert glycogen back into glucose. Thus, the blood glucose level is increased. The insulin of the β-cells and the glucagon of the α-cells thus act antagonistically, i.e. in opposition to each other. Type 2 diabetes is the result of a complex interaction of two causes:

  • Peripheral glucose resistance (impaired utilization of glucose) → insulin resistance (decreased response of body cells to the hormone insulin); this is the primary defect in the development of type 2 diabetes (see also Adiponectin in Obesity/The Adipose Tissue as an Endocrine Organ).
  • Insulin secretory dysfunction due to a multifactorial defect in β-cells (→ progressive β-cell dysfunction):
    • Chronic hyperglycemia (hyperglycemia) with consecutive increased formation of reactive oxygen radicals (glucotoxicity).
    • Reduced lipid oxidation and consequent accumulation of lipids as long-chain acyl coenzyme A (lipotoxicity).

Decreasing β-cell function creates an imbalance, between the α- and β-cells with a relative hyperfunction of α-cell function. This leads to relative hyperglucagonemia (→ hyperglycemia/increase in blood glucose). Note: The continuously deteriorating beta-cell function is reversible by radical weight reduction. In a study on this, patients with a mean duration of diabetes of three years were randomly assigned to either a weight reduction program or a group with standard therapy. The results were unequivocal: clinical remission of type 2 diabetes was achieved in 46 percent of subjects in the intervention group (versus 4 percent in the control group).Another study confirms this, highlighting that: substantial weight loss can reverse the underlying processes of type 2 diabetes; liver fat content is normalized and pancreatic fat content decreases in all cases; return to nondiabetic glucose control depends on the ability of β-cells to recover. The causes of type 2 diabetes mellitus have been known for a long time. They are essentially based on incorrect behavior:

  • Eating hypercaloric, high-fat meals (approximately 80-85% of all type 2 diabetics are overweight).
  • Lack of exercise (low physical activity)

Other factors include:

  • Reduced basal metabolic rate – with the same eating behavior and thus positive energy balance (= weight gain).
  • Reduced thermogenesis in old age
  • Decrease in functional reserve capacity of organ systems in old age:
    • Poorer absorption capacity of the intestine.
    • Decreased endocrine and exocrine pancreatic function.

Consequences of the above factors is the increase in abdominal (visceral) adipose tissue (so-called “apple type”). If necessary, see the sub-topic” The adipose tissue as an endocrine organ” under obesity/earth matters.

Etiology (causes)

Biographic causes

  • Genetic burden from parents, grandparents (heritability: strong).
    • If one parent has type 2 diabetes, 25-50 percent of children will also develop the disease; if both parents are type 2 diabetics, the risk increases to 60 percent
    • In type 2 diabetes, the genetic factor is much more pronounced, as the concordance in monozygotic (identical) twins is >90%, compared to circa 50% in type 1 diabetes. Despite this high concordance, the mode of inheritance is as yet unknown – apart from the rare diabetes form of MODY “maturity-onset diabetes of the young”, in which monogenic autosomal dominant inheritance has been demonstrated; * monogenic diabetes forms see below.
    • Genetic risk dependent on gene polymorphisms:
      • Genes/SNPs (single nucleotide polymorphism):
        • Genes: CDKAL1, HHEX, HNF1 alpha/4 alpha, IGF2BP2, KCNJ11, Kir6.2, PPARG, PPARγ, SGK1, SLC30A8, TCF7L2, mitochondrial genes.
        • SNP: rs5219 in the gene KCNJ11
          • Allele constellation: CT (1.3-fold).
          • Allele constellation: TT (2.5-fold)
        • SNP: rs7903146 in gene TCF7L2
          • Allele constellation: CT (1.4-fold).
          • Allele constellation: TT (2.0-fold)
        • SNP: rs13266634 in gene SLC30A8
          • Allele constellation: CT (1.2-fold).
          • Allele constellation: CC (1.44-fold)
        • SNP: rs1111875 in the gene HHEX
          • Allele constellation: AG (1.19-fold).
          • Allele constellation: GG (1.4-fold)
        • SNP: rs7754840 in the gene CDKAL1
          • Allele constellation: CG (1.3-fold).
          • Allele constellation: CC (1.3-fold)
        • SNP: rs4402960 in the gene IGF2BP2
          • Allele constellation: GT (1.2-fold).
          • Allele constellation: TT (1.2-fold)
        • SNP: rs1801282 in the gene PPARG
          • Allele constellation: CG (higher risk).
          • Allele constellation: GG (higher risk).
        • SNP: rs9402571 in the gene SGK1
          • Allele constellation: GT (slightly decreased risk).
          • Allele constellation: GG (0.85-fold)
  • Diseases (syndromes associated with diabetes)
    • Huntington’s chorea (synonyms: Huntington’s chorea or Huntington’s disease; older name: St. Vitus’ dance) – genetic disorder with autosomal dominant inheritance characterized by involuntary, uncoordinated movements accompanied by flaccid muscle tone.
    • Friedreich’s ataxia – genetic disease with autosomal recessive inheritance leading to a degenerative disease of the central nervous system.
    • Klinefelter syndrome – genetic disease with mostly sporadic inheritance: numerical chromosomal aberration (aneuploidy) of the sex chromosomes (gonosomal anomaly), which occurs only in boys or Men occurs; in the majority of cases characterized by a supernumerary X chromosome (47, XXY); clinical picture: large stature and testicular hypoplasia (small testis), caused by hypogonadotropic hypogonadism (gonadal hypofunction); here usually spontaneous onset of puberty, but poor pubertal progress.
    • Laurence-Moon-Biedl-Bardet syndrome (LMBBS) – rare genetic disorder with autosomal recessive inheritance; according to clinical symptoms is differentiated into:
      • Laurence-Moon syndrome (without polydactyly, i.e., without the appearance of supernumerary fingers or toes, and obesity, but with paraplegia (paraplegia) and muscle hypotonia/reduced muscle tone) and
      • Bardet-Biedl syndrome (with polydactyly, obesity and peculiarities of the kidneys).
    • Cystic Fibrosis (ZF) – genetic disease with autosomal recessive inheritance characterized by the production of secretions in various organs to be tamed.
    • Myotonic dystrophy type 1 (DM1; synonyms: myotonia dystrophica, dystrophia myotonica) – genetic disease with autosomal dominant inheritance; form of myotonic muscle disease with muscle weakness, cataract (cataract) and hypogonadism (hypogonadism).
    • Prader-Willi-Labhart syndrome (Prader-Willi syndrome) – genetic disease with autosomal dominant inheritance, which leads to various malformations such as acromicry (too small hands and feet) and hyperphagia (excessively increased food intake).
    • Porphyria or acute intermittent porphyria (AIP); genetic disease with autosomal dominant inheritance; patients with this disease have a 50 percent reduction in the activity of the enzyme porphobilinogen deaminase (PBG-D), which is sufficient for porphyrin synthesis. Triggers of a porphyria attack, which can last a few days but also months, are infections, drugs or alcohol. The clinical picture of these attacks presents as acute abdomen or neurological deficits, which can take a lethal course. The leading symptoms of acute porphyria are intermittent neurologic and psychiatric disturbances. Autonomic neuropathy is often prominent, causing abdominal colic (acute abdomen), nausea (nausea), vomiting, or constipation, as well as tachycardia (heart beats > 100 beats/min) and labile hypertension (high blood pressure).
    • Turner syndrome (synonyms: Ullrich-Turner syndrome, UTS) – genetic disorder that usually occurs sporadically; girls/women with this disorder have only one functional X chromosome instead of the usual two (monosomy X); a.o. Among other things, with an anomaly of the aortic valve (33% of these patients have an aneurysm/diseased bulging of an artery); it is the only viable monosomy in humans and occurs approximately once in 2,500 female newborns.
  • Fetal programming (epigenetic imprinting) by:
    • Preconceptional maternal obesity.
    • Diabetic metabolic state during pregnancy
    • Fetal growth restriction (IUGR, intrauterine growth restriction; fetal height and weight are below the 10th percentile) or fetal malnutrition – this increases the risk of impaired glucose tolerance in the offspring
  • Body size – normal weight and 10 cm more height: respectively, risk reduction of 86 percent in men and of 67 percent in women; in overweight participants, the risk reduction was only 36 and 30 percent, respectively.The authors see a possible cause in the association of body size and diabetes risk with the higher liver fat percentage of smaller people. Height – Normal weight and 10 cm more height: respectively, risk reduction of 86 percent in men and of 67 percent in women; in overweight participants, risk reduction was only 36 and 30 percent, respectively.The authors see a possible cause in the association of height and diabetes risk with the higher liver fat percentage of smaller people.
  • Hormonal factors – early menarche.
  • Socioeconomic factors – low social status.

Behavioral causes

  • Nutrition
    • Chronic overeating
      • High caloric intake
      • High-fat diet (saturated fat)
        • High proportion of saturated fatty acids
      • High intake of carbohydrates, especially mono- and disaccharides (monosaccharides and disaccharides) due to excessive consumption of sweets and sweet drinks: per serving of a soft drink (study mean 336 ml) per day, the risk of developing diabetes increased by 21%, per drink with artificial sweetener (eg. It is suspected that artificial sweeteners trigger hyperinsulinemia (a condition in which the concentration of the hormone insulin in the blood is increased above normal levels), which in turn increases the feeling of hunger and blocks lipolysis (fat burning).
    • High cholesterol intake
    • Excessive consumption of red meat, i.e. muscle meat of pork, beef, lamb, veal, mutton, horse, sheep, goat; 1.48 times the risk.
    • Excessive consumption of processed meat
    • Intake of grilled meat (red meat, chicken) or fish, i.e., preparation over an open flame and/or at high temperature → heterocyclic aromatic amines (HAAs), polycyclic aromatic hydrocarbons (PAHs), nitrosamines, and advanced glycation endproducts (AGEs).
    • Excess of acidifying foods
    • Too low a proportion of monounsaturated fatty acids
    • Too low a proportion of polyunsaturated fatty acids
    • Too low a proportion of complex carbohydrates
    • Diet low in fiber
    • Forgoing breakfast – strongest risk (+55%) when forgoing for 4-5 days per week.
    • Micronutrient deficiency (vital substances) – see prevention with micronutrients.
  • Consumption of stimulants
  • Physical activity
    • Physical inactivity – Even with pre-existing diabetes, regular physical activity can reduce the risk of secondary diseases such as cardiovascular disease and also reduce overall mortality (mortality).
    • Sitting for long periods (> 7.5 hours a day) – This increases the relative risk of developing type 2 diabetes mellitus by 112%.
  • Psycho-social situation
    • Traumatic childhood experiences: especially in people in whom four or more stressful factors, ranging from abuse to neglect, come together
    • High workload (job stress) and concomitant low control over activities performed; 45% higher risk of type 2 diabetes mellitus than people with low job stress
    • Shift work with night duty: diabetes risk correlated significantly with the number of years with night shifts: with one to five years by 11%, five to nine years by 28%, and ten or more years by 46%
  • Sleep duration
    • Children (age 9-10 years): average sleep duration 10.5 hours (8-12 hours); target is 10-11 hours; sleep duration showed an inverse correlation with HOMA index and fasting glucose (fasting blood glucose); each hour of increased sleep improved HOMA index by 2.9 percent (95 percent confidence interval 1.2 to 4.4 percent)
    • Adults: sleep deprivation (<4.5 hours of sleep; sleep deprivation produces feelings of hunger, decreases spontaneous exercise behavior, and insulin resistance)
    • Too little sleep (< 6 hours) impairs not only the metabolism of insulin, but also that of leptin – a satiety hormone – which also increases the risk of developing diabetes mellitus.
    • Prolonged sleep duration: increase of ≥ 2 h sleep per night compared with sleep duration sustained at 7 h was associated with increased risk of developing type 2 diabetes mellitus (“odds ratio” = 1.65 [95% CI (95% confidence interval) 1.15; 2.37]).
  • Television viewing and associated increased food intake (high energy density snacks and beverages) and physical inactivity.
  • Overweight (BMI ≥ 25; obesity).
    • There is a close association between obesity and type 2 diabetes mellitus, so it can be said that obesity is the most important manifesting factor of type 2 diabetes. Approximately 80-85% of all type 2 diabetics are overweight, and normal weight type 2 diabetics are the exception.
      • Independent risk factors in this context are:
        • Extent and duration of obesity
        • Recent pronounced increase in weight
    • Childhood obesity quadruples the risk of type 2 diabetes
    • Obesity is significantly more strongly associated with risk of type 2 diabetes than genetics
  • Android body fat distribution, that is, abdominal/visceral, truncal, central body fat (apple type) – high waist circumference or waist-to-hip ratio (THQ; waist-to-hip ratio (WHR)) is present When measuring waist circumference according to the International Diabetes Federation (IDF, 2005) guideline, the following standard values apply:
    • Men < 94 cm
    • Women < 80 cm

    The German Obesity Society published somewhat more moderate figures for waist circumference in 2006: < 102 cm for men and < 88 cm for women. Note: Not visceral fat depot, but intrahepatic fat (fat “inside the liver”) determines the degree of insulin resistance. (Decreased response of body cells to the hormone insulin). This explains why in obese people insulin sensitivity (insulin sensitivity) is not necessarily reduced.

Disease-related causes

  • Depression
  • Gestational diabetes/pregnancy diabetes (one in two women who had gestational diabetes during pregnancy developed type 2 diabetes mellitus permanently within 8 years after delivery).
  • Metabolic syndrome (abdominal obesity, insulin resistance (decreased response of the body’s cells to the hormone insulin), hyperinsulinemia (condition with an increased concentration of the hormone insulin in the blood above normal levels), impaired glucose tolerance, dyslipoproteinemia (lipid metabolism disorder), albuminuria (appearance of albumin in the urine)* , hypertension/high blood pressure).
  • Periodontitis (disease of the periodontium) → promotes the development of prediabetes as well as the transition from existing prediabetes to manifest diabetes
    • Patients with a depth of periodontal pockets ≥ 6 mm had a 56% increased risk of type 2 diabetes mellitus 15 years later (rate ratio 1.56; 0.84-2.92)
    • Likewise, periodontitis can significantly increase HbA1c levels!
    • Periodontal treatment improves the HbA1c value by 0.6 percentage points (95% confidence interval 0.3 to 0.9)
  • Steatosis hepatis (fatty liver).
  • Post-traumatic stress disorder (PTSD).
  • Pancreatic disorders
    • Cystic fibrosis (cystic fibrosis)
    • Pancreatitis (inflammation of the pancreas), acute and chronic; prevalence of chronic pancreatitis is 9.2% in the diabetic population
    • Pancreatic tumor (pancreatic tumor) or pancreatic carcinoma (pancreatic cancer); at the time of diagnosis “pancreatic carcinoma” 45-65% of patients already have diabetes mellitus.
    • Post-pancreatic resection (as a result of a reduction in beta cell mass).
    • Idiopathic hemochromatosis (iron storage disease).
    • Fibrocalcifying pancreatitis
  • Subclinical inflammation (English “silent inflammation”) – permanent systemic inflammation (inflammation that affects the whole organism), which proceeds without clinical symptoms.

* Characteristic only in the definition of WHO laboratory diagnoses – laboratory parameters that are considered independent risk factors.

  • Hypokalemia (potassium deficiency) in hypertensive (high blood pressure) patients is considered an early marker in prediabetes and type 2 diabetes mellitus.
  • LDL cholesterol < 60 mg/dl – 1.93-fold diabetes mellitus type 2 risk (comparison group with normal LDL-C: median concentrations 90-130 mg/dl)
  • Fasting insulin
  • Fasting glucose

Medications (with potential diabetogenic effects).

  • 5-alpha-reductase inhibitors (dutasteride, finasteride).
  • Alloxan
  • Alpha blockers, centrally acting
  • Antiarrhythmics
  • Antibiotics
    • Gyrase inhibitors (1st generation) – nalidixic acid.
    • Rifampicin
  • Antidepressants* *
    • Tricyclic antidepressants [insulin resistance ↑, weight gain]
  • Antiepileptic drugs
    • Phenytoin
  • Antihypertensives
    • Imidazolines (clonidine)
  • Antiprotozoal agents (pentamidine* , pentacarinate) [beta cell toxic effects].
  • Antipsychotics (neuroleptics)* * [insulin resistance ↑, weight gain]
  • Antiretroviral therapeutics
  • Arsenic trioxide
  • Benzothiadiazine derivatives (e.g., diazoxide) and analogues* * [→ potassium losses → insulin secretion ↓; effect is delayed, usually weeks to months after therapy).
  • Beta-blockers* * [increase in insulin resistance as a result of weight gain; inhibition of insulin secretion from beta cell and/or decreased muscle blood flow]
    • Nonselective beta blockers (eg, carvedilol, propranolol, soltalol) [inhibition of insulin secretion; more potent than selective beta blockers]
    • Selective beta-blockers (e.g., atenolol, bisoprolol, metoprolol).
  • Betamimetics (synonyms: β2-sympathomimetics, also β2-adrenoceptor agonists) – fenoterol, formoterol, hexoprenaline, ritodrine, salbutamol, salmeterol, terbutaline → hyperglycemia.
  • Chemotherapeutic agents/immunosuppressants.
    • Cycosporine A
    • Sirolimus (rapamycin)
    • Tacrolism
  • Dilantin*
  • Diuretics (risk increase approximately 23%).
  • H2 antihistamines (H2 receptor antagonists, H2 antagonists, histamine H2 receptor anatgonists) – cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine.
  • Hormones and hormonally active substances
    • ACTH
    • Antiestrogens (tamoxifen)
      • Nonmetastatic invasive breast carcinoma after antihormone therapy with tamoxifen → doubling of diabetes risk.
    • Aromatase inhibitor
      • Non-metastatic invasive breast carcinoma after anti-hormone therapy with aromatase inhibitor → quadrupling of diabetes risk.
    • Glucagon
    • Glucocorticoids* – betamethasone, budesonide, cortisone, fluticasone, prednisolone [insulin resistance ↑; altered cellular glucose metabolism]
    • Catecholamines
    • Prolactin
    • Thyroid hormones* – thyroxine
    • Sex steroids
    • Tokolytics
    • Growth hormone* (WH; somatropin; somatrophin) and analogues.
  • HIV therapy* *
    • Nucleoside analogue (didanosine) [pancreatitis.]
    • Protease inhibitors (indinavir, nelfinavir, ritonavir, etc.) [insulin secretion ↓, insulin resistance ↑; centripetal obesity with hypertriglyceridemia]
  • Indometacin
  • Immunosuppressants* * [insulin secretion↓]
  • Interferon-α* / alpha-interferon [induction of organospecific autoimmune disease/type 1 diabetes]
  • Lipid-lowering agents (risk increase approximately 32%); risk increase for menopausal women (hazard ratio [HR] 1.71, 95% CI, 1.61-1.83)
  • Morphine
  • MTOR inhibitors (everolimus, temsirolimus)
  • Nicotinic acid*
  • Psychoactive substances
    • Haloperidol
    • Imipramine
    • Lithium
    • Phenothiazide and derivatives
  • Streptozotocin [beta cell toxic effects.]
  • Sympathomimetics
    • Α-adrenergic agonists
    • Β-adrenergic agonists
  • Theophylline
  • Vacor* (pyrinuron, pyriminil; rodenticide) [beta cell toxic effects].
  • Vasodilators (diazoxide).
  • Cytostatics
    • Alkylants (cyclophosphamide)
    • L-asparaginase

* Directly diabetogenic * * Indirectly diabetogenic

Environmental exposure – intoxications (poisonings).

  • Bisphenol A (BPA) as well as bisphenol S (BPS) and bisphenol F (BPF).
  • Air pollutants
    • Particulate matter: long-term exposure to particulate matter in children (for every 10.6 µg/m³ of additional airborne nitrogen dioxide (NO2), the incidence of insulin resistance increased by 17%. For airborne particulate matter (up to 10 µm in diameter), there was a 19% increase in insulin resistance per 6 µg/m³).
  • Organic phosphates (OP) in insecticides: e.g., chlorpyrifos, dichlorvos (DDVP), fenthion, phoxim, parathion (E 605) and its ethyl and methyl derivatives, and bladane.
  • Pesticides

Other causes

  • Gravidity (pregnancy)

* Monogenic forms of diabetes

Notes for monogenic forms of diabetes:

  • Detection of diabetes within the first 6 months of life.
  • Occurrence of type 2 diabetes mellitus in multiple generations, each of which occurred at a young age and was not associated with obesity
  • When young, nonobese individuals have mild fasting hyperglycemia; or
  • When non-obese adults develop non-insulin-dependent diabetes without evidence of diabetic autoantibodies and without insulin resistance.

Note: Family history and phenotype are not reliable predictors of monogenic diabetes. For monogenic diabetes, see the review article by Hattersley and Patel.