Diabetes mellitus Prof. Dr. Borvendég János

Diabetes mellitus (DM) What is diabetes mellitus ? commonly referred to as diabetes, is a group of metabolic diseases in which there are high blood sugarlevels over a prolonged period. Symptoms of high blood sugar include frequent urination, increased thirst, and increased hunger.

Complications of diabetes mellitus Acut complications can include diabetic ketoacidosis,  hyperosmolar coma, or death.[  Serious long-term complications include heart disease, stroke, chronic kidney failure, foot ulcers, and damage to the eyes.

Cause of diabetes mellitus Diabetes is due to either -the pancreas not producing enough insulin -or the cells of the body not responding properly to the insulin.

Significance of diabetes mellitus. As of 2015, an estimated 415 million people had diabetes worldwide, with type 2 DM making up about 90% of the cases. This represents 8.3% of the adult population,with equal rates in both women and men. The No. of patients with diabetes in Hungary today about 300.000. As of trends suggested the rate would continue to rise all over the world.[

Main types of diabetes mellitus: Type 1 DM results from the pancreas's failure to produce enough insulin. This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes". The cause is unknown.]

Pathology of type 1 diabetes Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas, leading to insulin deficiency. This type can be further classified as immune-mediated or idiopathic. The majority of type 1 diabetes is of the immune-mediated nature, in which a  T-cell-mediated autoimmune attack leads to the loss of beta cells and thus insulin.[

Type 1 diabetes is partly inherited, with multiple genes, including certain HLA genotypes, known to influence the risk of diabetes  In genetically susceptible people, the onset of diabetes can be triggered by one or more environmental factors, such as a viral infection or diet

Type 2 DM begins with insulin resistance, a condition in which cells fail to respond to insulin properly. This form was previously referred to as "non insulin-dependent diabetes mellitus" (NIDDM) or "adult-onset diabetes".

In type 2 DM the defective responsiveness of body tissues to insulin is believed to involve the insulin receptor, but the specific defects are not known. Promoting factors are : not enough exercise,( physical activity), poor diet, stress, and urbanization.

Clinical symptoms   The classic symptoms of untreated diabetes are weight loss, polyuria (increased urination), polydipsia (increased thirst), and polyphagia (increased hunger).  Symptoms may develop rapidly (weeks or months) in type 1 DM, while the clinical symptoms of type 2 DM develop much more slowly and may be subtle or absent at the beginning.

Long term complications of diabetes. These typically develop after many years (10–20), but may be the first symptom in those who have otherwise not received a diagnosis before that time. damage to blood vessels. Diabetes doubles the risk of cardiovascular disease and about 75% of deaths in diabetics are due to coronary artery disease.[ Other "macrovascular" diseases are stroke, and peripheral vascular disease

Complications of DM ( cont.) The primary complications of diabetes due to damage in small blood vessels damage to the eyes, kidneys, and nerves.   diabetic retinopathy, is caused by damage to the blood vessels in the eye   diabetic nephropathy, can lead to tissue scarring, and   chronic kidney disease, sometimes requiring dialysis or kidney transplant

( cont.) diabetic neuropathy, is the most common complication of diabetes. The symptoms can include numbness, tingling, pain, and altered pain sensation, which can lead to damage to the skin.  Diabetes-related foot problems (such as diabetic foot ulcers) may occur, and can be difficult to treat, occasionally requiring amputation

Medical treatment of diabetes mellitus Insulin is the most common type of medication used in type 1 diabetes treatment. It’s also used in type 2 diabetes treatment. It’s given by injection and comes in different types. The type of insulin you need depends on how severe your insulin depletion is.

Insulin (from the Latin, insula meaning island) is a peptide hormone produced by beta cells of the pancreatic islets. It regulates: the metabolism of carbohydrates,  by promoting the absorption of, especially, glucose from the blood into fat, liver and skeletal muscle cells.

The place, and regulation of insulin production Insulin produced by the β cells of the pancreas) They are known to be sensitive to glucose concentrations in the blood. When it is high, β cells secrete insulin into the blood; when low they cease their secretion.

Glucagon Their neighboring alpha cells, by taking their cues from the beta cells, secrete glucagon into the blood in the opposite manner: increased secretion when blood glucose is low, and decreased secretion when glucose levels are high. Glucagon, stimulates the liver to release glucose by increasing the glyogenolysis and gluconeogenesis .Accordingly glucagon has the opposit effect of insulin.

Insulin consists of two polypeptide chains, the A- (21 aminoacids)and B-(30 amino acids) chains, linked together by disulfide bonds. It is however first synthesized as a single polypeptide called preproinsulin in pancreatic β-cells Phisiological function of insulin: Control of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about two-thirds of body cells) Increase of DNA replication and protein synthesis via control of amino acid uptake Modification of the activity of numerous enzymes.

Different types of insulin preparatios. Short-acting insulin regular insulin (Humulin and Novolin) Rapid-acting insulins insulin aspart(NovoLog, FlexPen) insulin glulisine (Apidra) insulin lispro (Humalog) Intermediate-acting insulin insulin isophane (Humulin N, Novolin N) Long-acting insulins insulin degludec (Tresiba) insulin detemir (Levemir) insulin glargine (Lantus)

Insulin lispro ( Humalog) It is a fast acting insulin analog. Engineered through recombinant DNA technology, the ultimate lysine and proline residues on the C-terminal end of the B-chain are reversed. This modification blocks the formation of insulin dimers and hexamers. This allowed monomeric insulin to be immediately available for postprandial injections. Insulin lispro has one primary advantage over regular insulin for postprandial glucose control. It has a shortened delay of onset, allowing slightly more flexibility than regular insulin

Insulin glargine Insulin glargine has a substitution of glycine for asparagine at N21 (Asn21) and two arginines added to the carboxy terminal of B chain. The arginine amino acids shifts the isoelectric point from a pH of 5.4 to 6.7, making the molecule more soluble at an acidic pH and less soluble at physiological pH. The glycine substitution prevents deamidation of the acid-sensitive asparagine at acidic pH. In the neutral subcutaneous space, resulting in a slow, peakless dissolution and absorption of insulin from the site of injection for at least 24 hours.

Insulin degludec It is an ultra-long acting insulin that, unlike insulin glargine, is active at a physiologic pH. The addition of hexadecanedioic acid to lysine at the B29 position allows for the formation of multi-hexamers in subcutaneous tissues.]This allows for the formation of a subcutaneous depot that results in slow insulin release into the systemic circulation.[7]

type 2. diabetes Pathology of type 2 diabetes In type 2 diabetes, the body either produces inadequate amounts of insulin to meet the demands of the body or insulin resistance has developed. Insulin resistance refers to when cells of the body such as the muscle, liver and fat cells fail to respond to insulin, even when levels are high.

Alpha-glucosidase inhibitors Acarbose inhibits enzymes (glycoside hydrolases) needed to digest carbohydrates, specifically, alpha-glucosidase enzymes in the brush border of the small intestines, and pancreatic alpha-amylase. Less glucose is absorbed because the carbohydrates are not broken down into glucose moleculesThis effect lowers your blood sugar levels. acarbose (Precose) miglitol (Glyset)

Sulfonylureas These are among the oldest diabetes drugs still used today. They work by stimulating the pancreas with the help of beta cells. hese drugs include: glimepiride (Amaryl) gliclazide glipizide (Glucotrol) glyburide (DiaBeta, Glynase, Micronase)

Like all sulfonylureas, glimepiride acts as an insulin secretagogue Risks of hypoglycemia. Glibenclamide (glyburide) is associated with an incidence of hypoglycemia of up to 20–30%, compared to as low as 2% to 4% with glimepiride. Glibenclamide also interferes with the normal homeostatic suppression of insulin secretion in reaction to hypoglycemia, whereas glimepiride does not.

Glipizide acts by partially blocking potassium channels among beta cells of pancreatic islets of Langerhans. By blocking potassium channels, the cell depolarizes which results in the opening of voltage-gated calcium channels. The resulting calcium influx encourages insulin release from beta cells.

Biguanides Biguanides make the tissues more sensitive to insulin, and help the muscles absorb glucose. The most common biguanide is metformin (Glucophage, Metformin Hydrochloride ERmetformin-alogliptin  

Metformin 1-(diaminomethylidene)-3,3-dimethyl-guanidine Metformin was discovered in 1922. Study in humans began in 1950 It was introduced as a medication in France in 1957 and the United States in 1995. .   It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic healthcare system The American Diabetes Association] recommends metformin as a first-line agent to treat type 2 diabetes.[

Metformin The exact mechanism of metformin is not completely understood. The drug's main effect is to decrease hepatic glucose production. Metformin also increases insulin sensitivity, which increases peripheral glucose uptake . Decreases the glucose absorption from the bowels.

DPP-4 inhibitors Glucagon increases blood glucose levels, and DPP-4 inhibitors reduce glucagon and blood glucose levels. The mechanism of DPP-4 inhibitors is to increase incretin levels (GLP-1 and GIP),which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.

DPP-4 inhibitors help the body continue to make insulin DPP-4 inhibitors help the body continue to make insulin. They work by reducing blood sugar without causing hypoglycemia (low blood sugar). These drugs can also help the pancreas make more insulin. These drugs include: linagliptin (Tradjenta) saxagliptin (Onglyza) sitagliptin (Januvia)

Sitagliptin Sitagliptin works to competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down the incretins GLP-1 and GIP, gastrointestinal hormones released in response to a meal.  By preventing GLP-1 and GIP inactivation, they are able to increase the secretion of insulin and suppress the release of glucagon by the alpha cells of the pancreas. This drives blood glucose levels towards normal.

Glucagon-like peptides (incretin mimetics) These drugs are similar to the natural hormone called incretin. They increase B-cell growth. They decrease your appetite. They also slow stomach emptying. albiglutide (Tanzeum) dulaglutide (Trulicity) exenatide (Byetta) liraglutide (Victoza)

Liraglutide (NN2211) is a long-acting glucagon-like peptide-1 receptor agonist, binding to the same receptors as does the endogenous metabolichormone GLP-1 that stimulates insulin secretion. Liraglutide improves control of blood glucose. It reduces meal-related hyperglycemia  by increasing insulin secretion (only) when required by increasing glucose levels, delaying gastric emptying, and suppressing prandial glucagon secretion

Meglitinides These medications help the body release insulin nateglinide (Starlix) repaglinide (Prandin)

Repaglinide lowers blood glucose by stimulating the release of insulin from the beta islet cells of the pancreas. It achieves this by closing ATP-dependent potassium channels in the membrane of the beta cells. This depolarizes the beta cells, opening the cells' calcium channels, and the resulting calcium influx induces insulin secretion.[

Sodium glucose transporter (SGLT) 2 inhibitors These drugs work by preventing the kidneys from holding on to glucose. Instead, ther body gets rid of the glucose through your urine. These drugs include: dapagliflozin (Farxiga) canagliflozin (Invokana) empagliflozin (Jardiance)

Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport proteins (SGLT2), which is responsible for at least 90% of renal glucose reabsorption (SGLT1Blocking this transporter causes up to 119 grams of blood glucose per day to be eliminated through the urine corresponding to 476 kilocalories. Additional water is eliminated by osmotic diuresis, resulting in a lowering of blood pressure. This mechanism is associated with a low risk of hypoglycaemia (too low blood glucose) compared to other types of anti-diabetic drugs such as sulfonylurea derivatives and insulin

Thiazolidinediones These medications work by decreasing glucose in the liver. They also help fat cells use insulin better. These drugs include: rosiglitazone (Avandia) pioglitazone (Actos)

Thiazolidinediones act as insulin sensitizers  Thiazolidinediones act as insulin sensitizers. They reduce glucose, fatty acid, and insulin blood concentrations. They work by binding to the peroxisome proliferator-activated receptors (PPARs) in fat cells and making the cells more responsive to insulin. . PPARs are transcription factors that reside in the nucleus and become activated by ligands such as thiazolidinediones. osiglitazone also appears to have an anti-inflammatory effect in addition to its effect on insulin resistance

hank you for your kind attention