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, a significantly increased risk of diabetes in the population is assumed. v.a. 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 consuming carbohydrate-rich food, blood sugar levels rise, causing increased insulin secretion. Insulin stimulates fat, liver, and muscle cells to absorb glucose from the blood, causing blood sugar levels to drop again.

Diabetes mellitus is the umbrella term for metabolic disorders caused by elevated blood sugar levels, resulting from an absolute deficiency or reduced effectiveness of the hormone insulin (relative deficiency). Due to the insulin deficiency, glucose can no longer be absorbed into the cells and thus 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), d.h. 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 caused by an autoimmune disease in which the body's immune system destroys the insulin-producing β-cells of the pancreas.
• Begins i.d.R. already in childhood/adolescence
• Is currently incurable, so that insulin injections must be administered 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
• Begins i.d.R. creeping and occurred earlier v.a. in old age (“adult-onset diabetes”), but now also increasingly in young adults and adolescents
• In addition to genetic disposition v.a. the following risk factors: 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 Glucose deficiency in target tissues and excess glucose in the blood.

What comorbidities and complications 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% hypertension
• 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/companion diseases in diabetes mellitus

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

Elevated glucose concentrations in the blood lead to a reaction between sugars and the body's own proteins – this is called glycosylation. The result is so-called AGEs ("advanced glycation end products" – these are cross-linked structural proteins), which the immune system then attempts to degrade. For this purpose, immune cells such as macrophages have receptors that recognize these AGEs (so-called "RAGE"). The glucose-induced increase in AGEs in the blood causes these receptors to be expressed in greater numbers, resulting in a macrophage-induced immune reaction and chronic inflammation, which in turn leads to oxidative stress and thus to the development of vascular damage.

The majority of diabetes-associated diseases arise from pathological changes in smaller (microangiopathy --> u.a. Retinopathy, nephropathy, neuropathy) and larger (macroangiopathy --> v.aAtherosclerosis (also known as atherosclerosis) affects blood vessels. Free radicals not only damage cellular membranes but also lead to changes in the structure and function of the affected vascular cells.

Oxidative phosphorylation, which occurs in the "powerhouses of our cells," the mitochondria, is also associated with the formation of oxygen radicals. In the case of an excess of glucose, dysregulation of mitochondrial metabolic processes leads to increased free radical formation. On the other hand, antioxidant protective enzymes are increasingly glycosylated, thus impairing their function.

Brownlee and colleagues have demonstrated 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 radical formation occurs. In their studies, they were able to demonstrate both the dependence of radical formation on substrate availability and the partial decoupling of mitochondrial electron flow between complexes 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 leading to vascular complications are activated. These include the activation of protein kinase C, the hexosamine pathway, the transcription factors NFκB and SP-1, and the reduced availability of nitric oxide (NO).

Oxidative stress also increases insulin resistance

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

This results in an increasingly complex system of insulin deficiency and oxidative stress.

In addition, in diabetes – v.a. 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.

If, however, 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 developing diabetes mellitus?

“Classic” risk factors:

• Metabolic syndrome
  • Lipid metabolism disorder
  • hypertension
  • Obesity/body fat distribution
• Unhealthy diet (--> oxidative stress)
• Lack of exercise (--> oxidative stress)
• Smoke (--> 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 u.a. psychogenic stress
• Oxidative stress = imbalance (radicals – antioxidants)

--> Domain of Orthomolecular Medicine

Evidence-based basic therapeutic measures of “lifestyle medicine”

• 8 weeks of medically supervised diet with only 600 kcal (only non-starchy vegetables and diet drinks) to 7 out of 11 patients with long-standing 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 fiber-rich fruits, vegetables, legumes, little red meat, more fish, more monounsaturated fats such as olive oil.
• “Diabetics must be informed about targeted supplementation of vital substances to prevent diabetic complications such as vision loss, amputations, stroke, and heart attack.”
  (Source: Prof. H.P. Meissner, diabetologist, Berlin, ÄP 4.10.2002)
• Of the The American Diabetes Association has officially recommended low-carb as an option for diabetes therapy since 2020: “...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 v.a. damage to kidneys, eyes and nerves caused by high osmotic pressure.
• Inhibits protein glycosylation (displaces glucose from protein binding sites) and thus the formation of AGE (with the o.g. negative effects). In cases 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 the synthesis of carnitine, neurotransmitters & collagen
• Reduces insulin resistance and HbA1c (an indicator of blood sugar levels over the past 2-3 months, as it shows the proportion of red blood cell 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 allows for increased transport of glucose into the cell.
• Lowers LDL cholesterolThe 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, allowing it to 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 blood vessels and thus improvement of blood circulation)

Diabetes patients have i.d.R. Vitamin C deficiency:

• Diabetic 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 absorption
• 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 individuals; diabetics need ~twice as much vitamin C! à "In order to achieve 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 supplement, attention must be paid to its bioavailability. With conventional supplements, only a small portion of the ingested vitamin C is actually available to the body. This is because, 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, a portion is excreted in 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 & -AggregationMayne 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 the effect of insulin (reduces insulin requirements)
• 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 by 4 times
• 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 the urine (glucosuria)
• Chronic illnesses, medication, 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 the
  Insulin at insulin receptor
• Inhibition of glycation, improvement of glucose tolerance (B1, B6)
• Homocysteine ​​reduction (B6, B12, folic acid)
• Cofactors for 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 a 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 (z.B. with one-sided diet, reduction diet)
• Reduced absorption in pancreatic insufficiency, malabsorption, high-fiber diet (zinc phytate complexes)

Relevance of zinc in relation to 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 binding ability to the insulin receptor
• Influences the enzyme carboxypeptidase B (catalyzes the conversion of proinsulin to insulin)
• Stimulates glucose metabolism in the muscles
• Promotes cellular glucose transport & glucose utilization
• Improves glucose tolerance & insulin sensitivity
• Zinc, along with copper and manganese, is a component of superoxide dismutase (SOD) – an enzyme important for the deactivation of free oxygen radicals
• Promotion of humoral & cellular immune defense
• Reducing 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 Tyrosine kinases are a group of enzymes from the protein kinase family whose function is the reversible transfer of a phosphate group (phosphorylation) to the hydroxyl 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 transduction as part of receptor systems.
• Involved in the formation of the glucose transporter GLUT (via signaling at the post-receptor level) à Glucose transporters (GLUT, SLC2A) are specific transmembrane transport proteins that catalyze the transport of glucose or fructose across the cell membrane. They are carrier protein-mediated uniports, with the glucose concentration gradient providing 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 (distributed over 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 is 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 lipid metabolism is the main cause of cardiovascular diseases associated with diabetes)
• Reduces ketone body formation; these occur v.a. in type 1 diabetes: If insulin is missing, not enough glucose reaches the cells from the blood, 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 (u.a. 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 reductaseAldose 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 v.a.Damage to kidneys, eyes and nerves caused by 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 &At <50 nmol/l, 100 mcg of vitamin D3 (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