Genetic predisposition to type 2 diabetes mellitus
If there are family members with type 2 diabetes mellitus, the risk of developing diabetes yourself is increased. For example, if both parents have type 2 diabetes mellitus, the likelihood that their children will also develop this type of diabetes is 70–80%. If one parent is affected, the risk for the child is up to 60%. Type 2 diabetes mellitus therefore has a genetic basis.
Type 2 diabetes: Lack of physical activity and overweight cause disease
For certain body cells, insulin acts as a signal to take up and process sugar (glucose) from the blood. To receive this signal, insulin binds to specific sites (insulin receptors) on the cell surface. In insulin resistance, these cells respond less to insulin. To keep blood sugar levels stable, more insulin is secreted from the beta cells. As a result, insulin levels in the blood increase (hyperinsulinism). Patients with type 2 diabetes mellitus therefore already have significantly higher insulin levels than healthy individuals before the onset of the disease and in its early stages.
Elevated insulin levels eventually lead to exhaustion of insulin production in the beta cells of the pancreas (see Fig. X1). Over time, this results in an insulin deficiency, and blood sugar levels continue to rise. The basis of treatment for type 2 diabetes mellitus therefore lies in lifestyle changes, i.e., weight reduction and increased physical activity.
Changes in insulin secretion, development of insulin resistance, and changes in blood glucose levels over the course of type 2 diabetes (modified from Diabetes Center Minneapolis 2001)This image was created using artificial intelligence.
The tendency to develop type 2 diabetes mellitus is inherited. Additional triggering factors include lack of physical activity, high-calorie diet, overweight, and, to a lesser extent, stress, certain medications, and infections. With increasing age, the likelihood of developing insulin resistance rises. Increased physical activity, a low-calorie diet, and weight loss can delay the onset of the disease and significantly mitigate its progression.
Insulin resistance usually develops slowly
As a result, blood sugar levels often rise unnoticed. Measurable disturbances in glucose metabolism often begin with slightly elevated morning fasting blood glucose values or elevated postprandial blood glucose values. Continuous glucose monitoring (CGM) can be used to observe this development, which is associated with an elevated HbA1c value (Fig. X2) [2]. This also allows the HbA1c value to be used in diagnosing diabetes (no diabetes: <5.7%, impaired glucose tolerance or elevated fasting blood glucose: 5.7 – <6.5%, diabetes: ≥6.5%), though it should be noted that there are a number of factors that can influence HbA1c (severe liver or kidney failure, hemolytic anemia, among others). If plasma glucose (random plasma glucose concentration ≥200 mg/dl [≥11.1 mmol/l]) and HbA1c are pathologically elevated, the diagnosis is confirmed [3].
From a morning fasting value of 110 mg/dl (6.1 mmol/l), the condition is referred to as impaired fasting glucose; from fasting values of 126 mg/dl (7.0 mmol/l) after 8 to 12 hours without food, it is classified as diabetes. The diagnosis is made by a physician.
The figure shows that type 2 diabetes mellitus does not have just one cause, but that the rise in blood glucose levels results from the interplay of many factors. The above description of the metabolic processes altered in patients with type 2 diabetes mellitus is probably still not complete, and further mechanisms are currently under investigation.
Despite the many different causes, the main problem remains overweight and lack of physical activity.
The figure above depicts the altered metabolic processes in type 2 diabetes mellitus. When carbohydrates are consumed in a meal, a food pulp (chyme) first forms in the stomach, and the carbohydrates then pass into the small intestine, where they are absorbed. The stomach itself absorbs only small amounts of carbohydrates. In the small intestine, the chyme stimulates the release of gastrointestinal hormones (GLP-1: glucagon-like peptide-1 and GIP: gastric inhibitory polypeptide or glucose-dependent insulinotropic peptide). These gastrointestinal hormones trigger insulin secretion from the pancreatic beta cells via a reflex pathway through the hypothalamus. Insulin lowers blood glucose. At the same time, glucagon release from the pancreatic alpha cells is suppressed. Glucose is stored in the liver in the form of glycogen. The hormone glucagon stimulates the breakdown of glycogen in the liver, allowing the liver to release glucose into the bloodstream. When gastrointestinal hormones suppress glucagon, less glucose is released into circulation. The action of gastrointestinal hormones is called the incretin effect. If too little GLP-1 and GIP are released from the chyme, blood glucose rises.
In addition, type 2 diabetes mellitus is associated with a defect in the beta cells (beta-cell defect). Not enough insulin is secreted to normalize blood glucose. In muscle tissue, there are receptors for the hormone insulin that enable glucose uptake into the muscle. In type 2 diabetes mellitus, there is insulin resistance, meaning that a larger amount of insulin is required for glucose to enter the muscle cell. If the beta cells cannot meet the increased insulin demand, blood glucose rises. When blood glucose exceeds 180 mg/dl (10.0 mmol/l), glucose is excreted by the kidneys. The kidney is therefore another important organ in blood glucose regulation. In both the kidney and the liver, glucose is newly produced (gluconeogenesis) during low blood glucose levels and released into the bloodstream.
This image was created using artificial intelligence.
When carbohydrates are consumed, the hormones GIP and GLP-1 are released from the mucosal lining of the small intestine. These so-called incretin hormones act on a receptor located on the nerves of the autonomic nervous system in the intestinal mucosa. This activates a reflex pathway via the hypothalamus (a control center in the brain). The nerves of the autonomic nervous system act on the beta cells in the islets of the pancreas, triggering immediate insulin release. This ensures that as soon as food is consumed, enough insulin is available for glucose to enter the cells and keep blood glucose levels stable. At the same time, incretin hormones suppress glucagon release from the alpha cells in the islets. Glucagon ensures that glucose is released from the liver and is therefore important for keeping blood glucose levels constant. Insulin from the beta cells acts directly on neighboring alpha cells to suppress glucagon release, preventing glucagon-induced liver glucose release from raising blood glucose further after food intake. Because patients with type 2 diabetes have inadequate insulin secretion, they also have insufficient suppression of glucagon during meals.
In patients with type 2 diabetes mellitus, the incretin effect is impaired. When these patients consume carbohydrates, less GIP and GLP-1 are released in the small intestine, and insulin release from the beta cells is reduced compared to healthy individuals. This results in a relative insulin deficiency that contributes to elevated blood glucose levels. Due to the lack of insulin, glucagon is also insufficiently suppressed, leading to glucose release from the liver even while dietary carbohydrates are being absorbed. This further increases blood glucose levels.
The discovery of the incretin effect by Michael Nauck led to the development of new medications. Analogs of GLP-1, the so-called GLP-1 receptor agonists (incretin mimetics), have been developed. These can partially restore the diminished incretin effect in patients with type 2 diabetes. Most GLP-1 RAs (e.g., exenatide, liraglutide, subcutaneous semaglutide) must be injected into the subcutaneous tissue because they are peptides—small protein molecules that would be digested in the stomach. However, an oral GLP-1 RA (oral semaglutide) is already approved in Europe but, as of May 2025, has not yet been launched in Germany. The manufacturer stabilized the active ingredient against enzymatic degradation and formulated it with an absorption enhancer. There is also a dual incretin mimetic (tirzepatide) that acts as an agonist at both the GLP-1 and GIP receptors.
GLP-1 is broken down within 1–2 minutes by the enzyme DPP-4 (dipeptidyl peptidase-4). Another group of medications has been developed to prevent this breakdown. By inhibiting DPP-4, GLP-1 levels in the intestinal mucosa and in the blood are increased. This helps partially restore the reduced incretin effect in type 2 diabetes, leading to increased insulin secretion after meals and stronger glucagon suppression, which together lower blood glucose levels.
Another effect of incretin hormones, via the reflex pathway of the autonomic nervous system, is delayed gastric emptying. This delay dampens the feeling of hunger. Without this delay, people tend to eat significantly more. This is why incretins not only lower blood glucose but also cause significant weight loss—up to 15% (e.g., semaglutide) [4] and over 20% (tirzepatide) [5]. For this reason, drugs such as semaglutide and tirzepatide are also approved for obesity treatment (BMI ≥ 30 kg/m²).
Insulin resistance is not the only cause of diabetes. Only 60% of overweight individuals develop diabetes. Forty percent of overweight people can produce enough insulin to keep blood glucose levels stable throughout life. In overweight individuals who do develop diabetes, there is an additional functional impairment of the beta cells: they cannot produce enough insulin to meet the body’s needs.
The kidney is also an important metabolic organ in diabetes. Glucose is initially freely filtered from the blood into the kidney’s small filters (glomeruli) and enters the tubules. In the tubules, a transport system reabsorbs most of this filtered glucose. If blood glucose levels exceed 180 mg/dl (10.0 mmol/l), not all the glucose is reabsorbed and some is excreted in the urine. This mechanism was once used to monitor the quality of diabetes control—treatment aimed at keeping urine glucose levels as low as possible. In type 2 diabetes, glucose reabsorption in the tubules is increased compared to healthy individuals, meaning more glucose is retained in the body, contributing to elevated blood glucose levels. The glucose transporters (SGLT2, SGLT1) in the tubules can be blocked with medications (SGLT-2 inhibitors, e.g., empagliflozin, dapagliflozin), thereby reducing glucose reabsorption from the primary urine.
The development of obesity, a key factor in diabetes onset, is partly caused by dysregulation in the brain. These mechanisms are still poorly understood. In the USA, bromocriptine, a dopamine agonist, is approved for the treatment of type 2 diabetes. Dopamine is a neurotransmitter— a substance that can stimulate nerve cells. Studies of migratory birds and hibernating mammals have shown that insulin resistance varies with the seasons. Dopamine plays a role in the seasonal regulation of insulin resistance. Increasing dopamine levels can reduce insulin resistance.
This image was created using artificial intelligence.
Category |
Key Points |
Genetics |
Strong hereditary component: Both parents affected → 70–80% risk for children; one parent affected → up to 60% risk. |
Pathophysiology |
Insulin resistance: body cells respond poorly to insulin → beta cells secrete more insulin → hyperinsulinism. |
Early Stage |
High insulin levels before and at onset of disease. |
Progression |
Chronic hyperinsulinism → beta cell exhaustion → insulin deficiency → rising blood sugar levels. |
Main Risk Factors |
Physical inactivity, overweight/obesity. |
Treatment Focus |
Lifestyle modification: weight reduction, increased physical activity. |
Therapeutic Goal |
Improve insulin sensitivity, preserve beta cell function, control blood glucose. |
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[2] Monnier L, Colette C, Dunseath GJ et.al. The loss of postprandial glycemic control precedes stepwise deterioration of fasting with worsening diabetes. Diabetes Care. 2007 Feb;30(2):263-9.
[3] Schwarz T, Niederau C, Pleus S, et.al. Definition, Klassifikation, Diagnostik und Differenzialdiagnostik des Diabetes mellitus: Update 2024. DDG-Praxisempfehlung. Diabetologie und Stoffwechsel 2024; 19: S125–S137
[4] Wilding JPH, Batterham RL, Calanna S, et.al. for STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989-1002.
[5] Liu L, Shi H, Xie M, et.al. Efficacy and safety of tirzepatide versus placebo in overweight or obese adults without diabetes: a systematic review and meta-analysis of randomized controlled trials. Int J Clin Pharm. 2024 Dec;46(6):1268-1280.