Basic Civil Engineering first year Notes- Chapter 4 Building.pptx
diabetes mellitus
1. Master Degree in Medical Biotechnologies
INTERNAL MEDECINE
DIABETES: THE BIOLOGICAL BASES OF
TREATMENT
2. DIABETES
DEFINITION: heterogeneous group of metabolic disorders that
share the phenotype of hyperglycemia
EPIDEMIOLOGY: diabetes prevalence is increasing worldwide,
it is similar in males and females and it is related with age:
• age < 20 years prevalence 0.19%
• age > 20 years prevalence 8.6%
• age > 65 years prevalence 20.1%
HEALTHCARE IMPACT: diabetes is the main cause of renal
failure, limbs amputation and blindness in adults (USA
epidemiologic data)
3. CLASSIFICATION
Type 1 Diabetes is characterized by insufficient insulin secretion
due to the loss of beta cells in Langherans Islets
• autoimmune (tipo IA)
• idiopathic (tipo IB)
Type 2 Diabetes is characterized by insulin resistence
• congenital (very uncommon)
• idiopathic (common, adult-onset, related with
obesity and metabolic syndrome).
4.
5.
6.
7. INSULIN
• Insulin is syntetized by b cells into the Langerhans islets (endocrine
pancreas); from the polypeptidic precursor, consisting of a single chain of
86 aa, the preproinsulin, through a proteolytic process, we obtain the
proinsulin and from this, for detachment of an internal peptide of 31 aa,
called C-peptide, insulin is obtained. The active hormone is formed by two
amino acid chains of 21 and 30 aa, called A and B chain respectively,
joined together by disulfide bridges
• Insulin is a small protein (PM 6 kDa) that is stored in the cytoplasm of b
cells within secretory vescicles
• Insulin secretion is stimulated by: plasma glucose concentration, gastrin,
GP-1, VIP, aa, vagus nerve.
• Insulin secretion is Ca2+ dependent and it is strictly dependent also by ATP
intracellular concentration
• Insulin secretion shows a pulsatile profile with small peaks, that occur
every 10 minutes, and large peaks, lasting 2-3 hours, induced by meals.
8. COUNTER-REGULATION OF INSULIN
SECRETION
Insulin secretion is inhibited when plasma glucose concentration is lower than
70 mg/dL
In addition to direct control exerted by plasma glucose there are several
hormones that antagonize insulin:
• GLUCAGON (secreted by alpha cells in pancreas islet)
• CATECHOLAMINES
• CORTISOL
9. breakfast dinnerlunch sleep
PlasmaInsulin
Modified from:
1. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.
2. Bolli GB et al. Diabetologia. 1999;42:1151-1167.
Basal secretion
Post-prandial secretion
NORMAL INSULIN SECRETION PROFILE
12. INSULIN EFFECTS
ANABOLIC EFFECT: Insulin determines internalization into
cells of glucose, FFA and aa, it activates enzymes involved in
glycogen synthesis, TG and proteins. Finally insulin inhibits
enzymes that degrade them
LIVER: Insulin increases glycogen, inhibits gluconeogenesis,
glycogenolysis, b-oxidation of fatty acids and ketogenesis
MUSCLE: Insulin increases the synthesis of insulin-
dependent glucose transporters (Glut-4) and induces its
translocation to the cell membrane, induces glycogen
synthesis, inhibits glycogenolysis.
ADIPOSE TISSUE: stimulates the storage of FFA in the form
of triglycerides, inhibits the hormone-sensitive lipase causing
block of hydrolysis of TG and fall of glycerol and FFA
plasma concentrations.
18. INSULIN RESISTANCE
• is defined as the decreased ability of insulin to act effectively
on target tissues (especially muscle, liver, and fat)
• is a prominent feature of type 2 DM and results from a
combination of genetic susceptibility and obesity.
• Insulin resistance may remain silent for a long time, since
supranormal levels of circulating insulin will normalize the
plasma glucose.
• Insulin resistance impairs glucose utilization by insulin-
sensitive tissues and increases hepatic glucose output; both
effects contribute to the hyperglycemia
19. • Insulin resistance and abnormal insulin secretion are central to the
development of type 2 DM.
• Insulin resistance precedes an insulin secretory defect but diabetes
develops only when insulin secretion becomes inadequate.
• Type 2 DM is polygenic and multifactorial, since in addition to
genetic susceptibility, environmental factors modulate the
phenotype.
• The genes that predispose to type 2 DM are incompletely
identified, but recent genome-wide association studies have
identified a large number of genes involved; the most prominent is a
variant of the transcription factor 7–like 2 gene
• Genetic polymorphisms associated with type 2 diabetes have also
been found in the genes encoding the peroxisome proliferators–
activated receptor-γ, potassium channel, zinc transporter, IRS, and
calpain 10.
TYPE 2 DIABETES MELLITUS
22. OBESITY AND INSULIN RESISTANCE
• Adipocytes secrete a number of biologic products
(nonesterified free fatty acids, retinol-binding protein 4, leptin,
TNF-α, resistin, and adiponectin)
• Adipokines modulate insulin sensitivity.
• The increased production of free fatty acids and some
adipokines may cause insulin resistance in skeletal muscle and
liver.
• Free fatty acids impair glucose utilization in skeletal muscle,
promote glucose production by the liver, and impair beta cell
function.
• In contrast, the production by adipocytes of adiponectin, an
insulin-sensitizing peptide, is reduced in obesity.and this may
contribute to hepatic insulin resistance.
23. • Adipocyte products and adipokines also produce an
inflammatory state and may explain why markers of
inflammation such as IL-6 and C-reactive protein are often
elevated in type 2 DM.
• In addition, inflammatory cells have been found infiltrating
adipose tissue. Inhibition of inflammatory signaling pathways
such as the nuclear factor κB (NF-κB) pathway appears to
reduce insulin resistance and improve hyper-glycemia in animal
models.
OBESITY AND INFLAMMATION
25. 1. Drugs that sensitize the
body to insulin and/or
control hepatic glucose
production
2. Drugs that stimulate the
pancreas to make more
insulin
3. Drugs that slow the
absorption of starches
Thiazolidinediones
Biguanides
Sulfonylureas
Meglitinides
Alpha-glucosidase
inhibitors
MAJOR CLASSES OF
MEDICATIONS
28. THIAZOLIDINEDIONES
• PPAR-g nuclear receptor agonists (peroxisome proliferator-
activated receptor g)
They increase the FFA storage in adipose tissue
reducing their circulating concentration
induce expression on the cell membrane and
translocation of Glut-4
reduce the adipocytes TNF-a release
29. In healthy subjects an
oral glucose load
stimulates an higher
insulin release (3-4
fold) with respect to iv
administration of the
same amount of
glucose. This “incretin
effect” is impaired in
patients with Type 2
diabetes.
INCRETIN EFFECT
30. GLP-1 and GIP are the two major incretin hormones found in
humans.
These incretins are released from the gut in response to ingestion
of food and collectively contribute to glucose control by:
Stimulating glucose-dependent insulin release from
pancreatic beta cells (GLP-1 and GIP); insulin increases glucose
uptake in peripheral tissues (mainly muscle and fat) and
suppresses glucose production from the liver.
Decreasing glucagon production from pancreatic alpha cells
(GLP-1) when glucose levels are elevated.
INCRETINS
31. GLP-1 (glucagon-like
peptide 1)
• Produced by L cells in
ileum and in colon
GIP (glucose-dependent
insulinotropic polypeptide)
• Produced by K cells in
duodenum and proximal
jejunum
INCRETINS
dipeptidyl peptidase-4 (DPP-4)
• Enzyme that rapidly inactivates endogenous
GLP-1 and GIP
• Its inhibition enhances and prolongs the actions
of both GLP-1 and GIP.
34. • Binds GLP-1 receptor
• More resistant than GLP-1 to the action of
DPP-4
• Originally isolated from Gila monster
saliva
I have never been called to attend a case of Gila monster
bite, and I don't want to be. I think a man who is fool
enough to get bitten by a Gila monster ought to die. The
creature is so sluggish and slow of movement that the
victim of its bite is compelled to help largely in order to get
bitten.
—Dr. Ward, Arizona Graphic, September 23, 1899
EXENATIDE
35. • Orally active DPP-4 inhibitor
• Prolungues and enhances the action
of endogenous GLP-1 and GIP.
SITAGLIPTIN
36. BRIEF INSULIN HISTORY
• Langerhans described pancreatic islets in the second half of the nineteenth
century
• after a few years it has been observed that dogs developed a syndrome
similar to DM after pancreatectomy
• in the early '900 has been observed that the administration of
hydroalcoholic extracts of pancreas was able to determine the reduction of
glycosuria in diabetic dogs
• in 1922 Banting and Best (Toronto) treated the first DM patient with
pancreatic islets extract
• Banting and Macleod, an expert in chemical extraction techniques, began to
develop a method that was used to obtain stable extracts of insulin and this
led them to win the Nobel Prize for Medicine in 1923
37. INSULIN TREATMENT
• after insulin discovery patients were treated with insulin preparations from porcine
or bovine pancreatic extracts for >70 years; these hormones were characterized by
immunogenicity because they present some differences in aa sequences with respect
to human insulin (1 and 3 aa respectively)
• with the advent of human insulin, beef and pork insulin are no longer produced
• Human insulin is produced by recombinant DNA technology
• In 1978 insulin became the first human protein to be manufactured through
biotechnology. A team of researchers from the City of Hope National Medical
Center and the biotechnology company Genentech managed to synthesize human
insulin in the laboratory using a process that could produce large amounts.
The team inserted the gene for human insulin into bacterial DNA, and used the
bacteria as miniature factories to make the A and B chains of the protein separately.
In a second step, a chemical process combined them. The result was human insulin,
without the problems animal insulin sometimes causes.
• Humulin, as the commercial product was called, revolutionized diabetes treatment
when it became widely available in the early 1980s. Today, almost all diabetic
people use recombinant human insulin instead of animal insulin.
38. Two approaches are used to modify the absorption and
pharmacokinetic profile of insulin.
• The first approach, which has been used for >70 years to alter
the absorption profile of native insulin, is based on formulations
that slow the absorption following subcutaneous injection.
• The other approach is to alter the amino acid sequence or protein
structure of human insulin so that it retains its ability to bind the
insulin receptor, but its behavior in solution or following injection
is either accelerated or prolonged in comparison to native or
regular insulin
INSULIN FORMULATION
40. CHEMICAL MANIPULATION
• Slow insulin NPH (neutral protamine Hagedorn) o isophane
insulin suspension: zinc and protamine complexed insulin
suspension in phosphate buffer
• Because of this formulation, the insulin dissolves more gradually
when injected subcutaneously and thus its duration of action is
prolonged. NPH insulin is usually given either once a day (at
bedtime) or twice a day in combination with short-acting insulin.
41. GENETIC MANIPULATION
• Short-acting insulin analogs (lispro, aspart, glulisine) dissociates into
monomers almost instantaneously following injection. This property results in
the characteristic rapid absorption and shorter duration of action compared
with regular insulin. Two therapeutic advantages have emerged with these
analogs as compared with regular insulin: the prevalence of hypoglycemia is
reduced and glucose control is modestly but significantly improved.
• Slow-acting insulin analog (glargine or LANTUS) is a long-acting analog of
human insulin that is produced following two alterations of human insulin.
Two arginine residues are added to the C terminus of the B chain, and an
asparagine molecule in position 21 on the A chain is replaced with glycine.
Insulin glargine is a clear solution with a pH of 4.0, which stabilizes the
insulin hexamer. When injected into the neutral pH of the subcutaneous
space, aggregations occurs, resulting in prolonged, but predictable, absorption
from the injection site. In clinical studies glargine has a sustained peakless
absorption profile, and provides a better once-daily 24-hour insulin coverage
than NPH insulin.