How many people in Germany are affected by diabetes?

Currently, at least 8.7  million people have type 2 diabetes and 32,000  children and young people and 340,000  adults have type 1 diabetes. Due to pandemic control measures (including lockdowns) in 2020/2021, there is a significantly increased risk of diabetes in the population, especially due to reduced physical activity and weight gain. (Source: https://www.diabetesde.org/system/files/documents/gesundheitsbericht_2023_final.pdf)

What exactly is diabetes mellitus?

After eating a carbohydrate-rich food, the blood sugar level rises, causing more insulin to be released. Insulin stimulates fat, liver and muscle cells to absorb glucose from the blood, causing the blood sugar level to fall again.

Diabetes mellitus is the general term for metabolic disorders caused by elevated blood sugar levels, which result from an absolute lack of or reduced effect of the hormone insulin (relative deficiency). Due to the insulin deficiency, glucose can no longer be absorbed into the cells and therefore can no longer be used as an energy source. Instead, glucose accumulates in the blood.

Above a certain concentration, increased amounts of glucose are excreted via the kidneys/urine, resulting in water and electrolyte loss.

What is the difference between type 1 and type 2 diabetes?

At a absolute insulin deficiency (IDDM) we speak of type 1 diabetes, at a relative insulin deficiency or insulin resistance one speaks of type 2 diabetes (NIDDM), ie the target tissues primarily respond inadequately to secreted insulin.

type 1 diabetes

• Absolute insulin deficiency because the pancreas does not produce enough insulin
• It is an autoimmune disease in which the body's own immune system destroys the insulin-producing β-cells of the pancreas.
• Usually begins in childhood/adolescence
• There is currently no cure, so insulin injections are required for life

type 2 diabetes

• Causes reduced sensitivity of the body's cells to insulin (insulin resistance) and "exhaustion" of insulin-producing cells in the pancreas due to years of overproduction of insulin
• Usually begins gradually and used to occur mainly in old age (“adult-onset diabetes”), but now also increasingly in young adults and adolescents
• In addition to genetic predisposition, the following risk factors are particularly important: lack of exercise, obesity, unbalanced diet (low in fiber and high in fat and sugar) and smoking

The consequence of both forms of diabetes is a glucose deficiency in target tissues and glucose excess in the blood.

What accompanying and secondary diseases occur in diabetes mellitus?

The Diabetes Health Report provides an overview of the frequency of occurrence of concomitant and secondary diseases at 120.000 type 2 diabetics cared for:

• 75.2% high blood pressure
• 11.9% diabetic retinopathy
• 10.6% neuropathy
• 9.1% heart attack
• 7.4% peripheral arterial occlusive disease (PAD)
• 4.7% stroke
• 3.3% nephropathy (renal insufficiency)
• 1.7% diabetic foot syndrome
• 0.8% amputation
• 0.3% blindness

Oxidative stress as a central cause of many secondary/comorbidities in diabetes mellitus

All available parameters that are considered as indirect measures of oxidative stress (direct measurement is not possible in vivo) are increased in diabetic patients. Therefore, the formation of free radicals as a consequence of oxidative stress is now considered the central biochemical explanation for diabetes-associated diseases (cf. Davi et al., Ceriello et al.).

Increased glucose concentrations in the blood lead to a reaction between sugars and the body's own proteins - this is called glycosylation and the result is so-called AGEs ("Advanced Glycation Endproducts" - these are cross-linked structural proteins), which the immune system then tries to break down. For this purpose, immune cells such as macrophages have receptors that recognize these AGEs (so-called "RAGE"). Due to the glucose-induced increase in AGEs in the blood, these receptors are formed in greater numbers and a macrophage-induced immune reaction and chronic inflammation occur, which in turn leads to oxidative stress and thus to the development of vascular damage.

The majority of diabetes-associated diseases are caused by pathological changes in smaller (microangiopathy --> including retinopathy, nephropathy, neuropathy) and larger (macroangiopathy  --> especially atherosclerosis) blood vessels. Free radicals not only damage cellular membranes, but also lead to changes in the structure and function of the affected vascular cells.

The oxidative phosphorylation that takes place in the "power plants of our cells", the mitochondria, is also associated with the formation of oxygen radicals. If there is an excess of glucose, free radicals are increasingly formed due to a dysregulation of mitochondrial metabolic processes. On the other hand, antioxidant protective enzymes are increasingly glycosylated and thus their function is impaired.

Brownlee and colleagues have succeeded in proving that overloading vascular cells with substrates such as glucose (hyperglycemia) and fatty acids (hyperlipidemia) increases mitochondrial electron flow (in the electron transport or respiratory chain) to such an extent that massive free radicals are formed. In their studies, they were able to demonstrate both the dependence of radical formation on the substrate supply and the partial decoupling of mitochondrial electron flow between complex II and III of the respiratory chain. At the same time, they were able to show that as a result of mitochondrial radical formation, diabetes-specific signaling pathways that lead to vascular complications are activated. These include the activation of protein kinase C, the hexosamine metabolic pathway, the transcription factors NFκB and SP-1, and the reduced availability of nitric oxide (NO).

Oxidative stress also increases insulin resistance

Free radicals as a result of oxidative stress and their cytotoxic effects also contribute to the death of β-cells in the pancreas through apoptosis, so that the synthesis of insulin is further impaired and insulin deficiency occurs.Insulin-dependent uptake of glucose by adipocytes and L6 muscle cells is impaired when these cells are exposed to oxidative stress.

This results in a reinforcing system of insulin deficiency and oxidative stress.

In addition, in diabetes - especially in a large number of elderly patients - a reduced antioxidant capacity contributes to the increase of oxidative stress, since the supply of antioxidants such as vitamin C, E, coenzyme Q10 or polyphenols such as quercetin, resveratrol, OPC etc. is often inadequate, especially in old age.

However, if oxidative stress is regulated by antioxidants, insulin-dependent glucose uptake by the cells is normalized again (cf. Klip et al).

What are the typical risk factors for the development of diabetes mellitus?

“Classic” risk factors:

• metabolic syndrome
  • lipid metabolism disorder
  • hypertension
  • overweight/body fat distribution
• Unfavorable diet (--> oxidative stress)
• lack of exercise (--> oxidative stress)
• Smoking (--> oxidative stress)

--> domain of "lifestyle medicine"

Risk factors that can be influenced by micronutrients:

• (chronic) inflammation ("silent inflammation")
• hyperhomocysteinemia
• Nitrogen imbalance, ADMA elevation and relative arginine deficiency
• Disorders of mitochondrial function
• Increase in Lp(a), fibrinogen and plasmin activator
• Disturbance of erythrocyte and platelet function
• Stress, depression and other psychogenic stress
• Oxidative stress = imbalance (radicals – antioxidants)

--> domain of orthomolecular medicine

Evidence-based basic therapeutic measures of “lifestyle medicine”

• 8 weeks of medically supervised nutrition with only 600 kcal (only non-starchy vegetables and diet drinks) à 7 out of 11 patients with long-term type 2 diabetes (insulin production and liver function are normalized) are cured of their disease. In addition, it has long been known that every second patient who loses 10 kg soon after being diagnosed with diabetes will recover.
  (Sources: Lim EL et al.; Reversal of type 2 diabetes: normalization of beta cell function in association with decreased pancreas and liver triacylglycerol; Diabetologia 2011; doi: 10.1007/s00125-011-2204-7; SZ July 1, 2011
• High sugar consumption promotes obesity, type 2 diabetes, dyslipidemia, hypertension and cardiovascular diseases (Sources: prospective study of 11,733 adults; JAMA Intern Med. 2014 Apr;174(4):516-24. doi: 10.1001/jamainternmed.2013.13563. Added sugar intake and cardiovascular diseases mortality among US adults. Yang Q1, Zhang Z1, Gregg EW2, Flanders WD3, Merritt R1, Hu FB4.)
• A "Mediterranean" diet is beneficial with a high proportion of fibre-rich fruits, vegetables, legumes, little red meat, more fish, more monounsaturated fats such as olive oil.
• “Diabetics must be informed about the targeted supplementation of vital substances to prevent diabetic complications – loss of vision, amputations, stroke and heart attack.”
  (Source: Prof. HP Meissner, diabetologist, Berlin, ÄP 4.10.2002)
• Of the Since 2020, the American Diabetes Association has officially recommended low-carb as an option for diabetes therapy: “...Reducing overall carbohydrate intake for individuals with diabetes demonstrated the most evidence for improving glycemia and may be applied in a variety of eating patterns that meet individual needs and preferences. For individuals with type 2 diabetes not meeting glycemic targets or for whom reducing glucose-lowering drugs is a priority, reducing overall carbohydrate intake with a low- or very-low-carbohydrate eating pattern is a viable option..." (Source: https://care.diabetesjournals.org/content/43/Supplement_1/S48.full-text.pdf)

Which micronutrients / dietary supplements are relevant for diabetes mellitus?

vitamin C

• Vitamin C inhibits the enzyme aldose reductase (AR) and thus the formation of sorbitol (Aldose reductase is an enzyme that converts glucose to sorbitol). In diabetes mellitus, AR produces a lot of sorbitol, which accumulates in the cells and causes damage to the kidneys, eyes and nerves due to the high osmotic pressure.
• Inhibits protein glycosylation (displaces glucose from protein binding sites) and thus the formation of AGE (with the negative effects mentioned above). In case of vitamin C deficiency, the glycosylation rate is increased!
• Most important water-soluble antioxidant
  • Reduces free radicals resulting from oxidative stress
  • Protects folic acid & vitamin E from oxidation
• Important for synthesis of carnitine, neurotransmitters & collagen
• Reduces insulin resistance and HbA1c (indicator of blood sugar over the last 2-3 months, as it shows the proportion of red blood pigment to which sugar is bound). Vitamin C intake increases the concentration of reduced glutathione in the plasma, which causes a change in membrane permeability. This results in improved insulin effectiveness, which enables increased transport of glucose into the cell.
• Lowers LDL cholesterol: The reduction in LDL cholesterol can be explained by the fact that vitamin C, with its antioxidant effect, protects LDL cholesterol from non-enzymatic glycosylation and peroxidation, so that it can be broken down unhindered. The concentration of HDL cholesterol, the so-called "good" cholesterol, remains unaffected by the increased vitamin C intake.
• Improves (endothelium-dependent) vasodilation (= expansion of the blood vessels and thus improvement of blood circulation)

Diabetes patients usually have a vitamin C deficiency:

• Diabetes patients have at least 30% lower Vit C levels (Nutr Rev 1996; 57; 193-202)
• HbA1c and Vit C levels correlate inversely (Diab Care 2000; 23; 726-732)

Causes of Vitamin C Deficiency in Diabetes

• Increased vitamin C requirement due to oxidative stress
• Hyperglycemia inhibits active vitamin C uptake
• Diabetics have approx.50% reduced storage capacity for vitamin C

Typical dosage: 500-2000 mg (spread over several portions) over 4 months; the aim is to achieve a level similar to that of healthy people; diabetics need ~twice as much vitamin C! à “In order to be able to determine the positive effects of vitamin C described in the studies, a vitamin C intake of 500 to 1000 mg per day is necessary. When taking a high-dose vitamin C preparation, it is important to pay attention to its bioavailability. With conventional preparations, only a small part of the amount of vitamin C taken in is actually available to the body, since on the one hand the absorption rate decreases with increasing dosage and on the other hand if the vitamin C blood level rises too quickly and too high, part of it is eliminated via the urine."
(cf. https://www.deutsche-apotheker-zeitung.de/daz-az/1997/daz-42-1997/uid-2313)

vitamin E

• Most important fat-soluble antioxidant
• Inhibits oxidation of lipids, enzymes & hormones (increased lipid peroxidation in diabetics
  through increased glycosylation of plasma proteins)
• Reduces platelet adhesiveness & aggregation: Mayne et al. (1970) and Jäger et al. (1975) demonstrated significantly higher platelet stickiness in diabetics compared to normal subjects.
• Reduces protein glycolysis and thus AGE formation
• Reduces thromboxane synthesis (thromboxane activates platelet aggregation)
• Improves insulin effect (reduces insulin requirement)
• Reduces risk of retinopathy and nephropathy
• Reduces fatal heart attacks by 77% (Source: Chaos Study 1996)
• Vitamin E requirement increased in diabetes
• Low vitamin E levels increase diabetes risk 4-fold
• Typical dosage: 100-600 mg per day

B vitamins

Possible causes of B vitamin deficiency in diabetes:

• Insufficient intake, poor diet, high consumption
• Increased excretion in urine (glucosuria)
• Chronic diseases, medication intake, if necessaryincreased alcohol consumption

Relevance of B vitamins in relation to diabetes:

• Water-soluble coenzymes in carbohydrate, amino acid and fat metabolism (B1, B2, B3, B5, B6, folic acid)
• Antioxidant effect (B2, B3)
• Important for nerve metabolism (“neurotropic”): Improvement of pain and nerve conduction velocity (B1, B6, B12)
• Regeneration of B cells, formation of glucose tolerance factor (B3)à mediates binding of
  insulin at insulin receptor
• Inhibition of glycolysis, improvement of glucose tolerance (B1, B6)
• homocysteine ​​reduction (B6, B12, folic acid)
• Cofactors of energy production in the mitochondria (B1, B2, B3, B5)
• DNA synthesis (B12)
  (Sources: Arzneimittel-Forschung 1990; 49, 220-224; Exp Clin Endocrinol Diabetes 1996; 104; 311-316)

Typical dosage: best one high-dose B complex, because B vitamins activate each other

zinc

Possible causes of zinc deficiency in diabetes:

• Increased zinc excretion via urine (2-3x more)
• Low zinc intake (e.g. with a one-sided diet, reduction diet)
• Reduced absorption in pancreatic insufficiency, malabsorption, high-fiber diet (zinc-phytate complexes)

Relevance of zinc in diabetes: Reduces NBZ & HbA1c & insulin requirements

• Important for insulin production in alpha and beta cells of the pancreas; stabilizes the structure of crystalline insulin (insulin storage in the form of a zinc-insulin complex)
• Increases the binding ability to the insulin receptor
• Influences the enzyme carboxypeptidase B (catalyzes conversion of proinsulin to insulin)
• Stimulates glucose metabolism in the muscles
• Promotes cellular glucose transport & glucose utilization
• Improves glucose tolerance & insulin sensitivity
• Along with copper and manganese, zinc is a component of superoxide dismutase (SOD) – an enzyme important for the deactivation of free oxygen radicals
• Promotion of humoral & cellular immune defense
• Reduction of wound healing disorders in diabetes

Typical Dosage: 10-25 mg/day - initially up to 3 x 25 mg/day

magnesium

• Improves insulin sensitivity and reduces insulin resistance
• To be used before the onset of diabetes (in case of insulin resistance)
• Controls tyrosine kinase at the insulin receptor à Tyrosine kinases are a group of enzymes from the protein kinase family whose task is the reversible transfer of a phosphate group (phosphorylation) to the hydroxy group of the amino acid tyrosine of another protein. This significantly influences the activity of the target protein, which is why tyrosine kinases also make an important contribution to signal transmission as part of receptor systems.
• Involved in the formation of the glucose transporter GLUT (via signal transduction at the post-receptor level) à Glucose transporters (GLUT, SLC2A) are certain transmembrane transport proteins that catalyze the transport of glucose or fructose through the cell membrane. They are carrier protein-mediated uniports, whereby the concentration gradient of glucose provides the energy required for transport.
• Influences enzymes that regulate glucose utilization
• Also protects against coronary heart disease (Lack of oxygen in the heart due to narrowed coronary arteries)
• Typical dosage: 240-900 mg (divided into several doses)

coenzyme Q10

• Diabetes = Q10-consuming disease
  • Majority of diabetics have Q10 deficiency
  • Increased glycosylation leads to the inactivation of many antioxidant enzymes (catalase, superoxide dismutase (SOD))
• Q10 improves metabolic parameters
• Q10 improves blood pressure and blood sugar control
• Q10 important for energy production in the mitochondria (electron transport chain), protection against radicals, membrane stabilization
• Typical dosage: 5-100 mg (depending on the bioavailability of the supplement used)

L-carnitine

• improvement of glucose metabolism by increasing glycogen synthase activity (with increased glucose utilization and decreased insulin resistance) and glucose release
• improvement of diabetic dyslipoproteinemia (increased concentration of triglycerides, reduced levels of “good” HDL cholesterol and a predominance of “bad” LDL cholesterol; this disorder of fat metabolism is the main cause of cardiovascular diseases associated with diabetes)
• Reduces ketone body formation; these occur mainly in type 1 diabetes:  If insulin is missing, not enough glucose gets from the blood into the cells, so that fat is burned in the mitochondria instead of sugar.  This produces ketone bodies, which in large quantities can lead to ketoacidosis (a severe metabolic disorder resulting from overacidification caused by ketone bodies).
• Stabilization of nerve cell membranes (improvement of vibration sensation and pain)
• Typical dosage: 200-800 mg/day

Alpha-lipoic acid (contained in Anti-Ox)

• Antioxidant: Reduces lipid peroxidation (including in nerve tissue)
• biocatalyst for energy metabolism (ATP enrichment)
• Inactivates radicals and regenerates vitamin C & E (redox recycling)
• Coenzyme of pyruvate dehydrogenase (catalyzes conversion of pyruvate to acetyl coenzyme A in the mitochondria)
• Inhibits protein glycosylation and thus the formation of AGEs
• Inhibits aldose reductase; Aldose reductase (AR) is an enzyme that converts glucose to sorbitol.In diabetes mellitus, AR produces a lot of sorbitol, which accumulates in the cells and causes damage to the kidneys, eyes and nerves due to the high osmotic pressure.
• Improves glucose utilization (Stimulation of glucose uptake in muscle cells like insulin)
• increase in glutathione
• Improves polyneuropathy
• Typical dosage: 0.2-1 g

vitamin D

Randomized, controlled, double-blind study with 81 participants over 6 months:
"In insulin-resistant women with vitamin D levels < 50 nmol/l, vitamin D3 100 mcg (4000 IU) significantly reduces insulin resistance. The best results were found at vitamin D levels of 80-119 nmol/l."
Source: By Hurst PR et al.; Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient – ​​a randomized placebo-controlled trial. British Journal of Nutrition 2009; First View article, doi: 10.1017/S0007114509992017

resveratrol

• Study from 2014: Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials. Liu K1, Zhou R1, Wang B1, Mi MT1.
  RESULTS: Eleven studies comprising a total of 388 subjects were included in this meta-analysis. CONCLUSIONS: Resveratrol significantly improves glucose control and insulin sensitivity in persons with diabetes […]. Additional high-quality studies are needed to further evaluate the potential benefits of resveratrol in humans.
• Typical dosage: 500 mg/day