1. Treatment of diabetes mellitus (1)
Pancreas:
Has exocrine function → digestive enzyme.
Has endocrine function → peptide hormones from islets of langerhans as:-
β cells:- produce insulin C-peptide, proinsulin, islets amyloid polypeptide (IAPP or amylin) whose function is undefined.
α2 or A cells:- produce glucagon → hyperglycemia by mobilization of glycogen stores.
α1 or D cells:- produce somatostatin → hyperglycemia by inhibition of secretory cells.
These hormones play an important role in regulating the metabolic activities of the body, particularly the homeostasis of blood glucose

2. Insulin:
A simple protein consisting of 51 A.A. arranged in 2 polypeptide chains, A and B, connected by disulfide bonds.

3. ,

5. Other factors → release of insulin:
Other carbohydrates e.g. mannose, ribose.
A.A.
Hormones e.g. gastrin, cholecystokinin, (G.H.), incretin, pancreozymin ……...glucagon
Somatostatin → inhibit β cells product.
Cholinergic stimulation → ↑ insulin.
Adrenergic stimulation → ↓ insulin secretion.
Insulin T1/2 ≈ 3-5 min.
The release characterized by a rapid initial secretion of insulin (lacked in D.M.), and followed by secondary more slowly decaying release (biphasic release).
Hyperinsulinemia (due, for example, to an insulinoma) can cause severe hypoglycemia.
A rela-tive or absolute lack of insulin, such as in diabetes mellitus, can cause
serious hyperglycemia. If this condition is left untreated, retinopathy, nephropathy, neuropathy, and cardiovascular complications may result.

7. After release, insulin bind special receptors on the membrane of most tissues (mainly in liver, muscles, adipose tissue) to produce biological effects.
Then, degradation occurs in the liver by Tyrosine kinase. Insulinase (60%) and further degradation in kidney by proteolytic enzyme.
In conditions associated with ↑ insulin level e.g. obesity and insulinoma → down regulation of insulin receptors → state of insulin resistance.
Insulin resistance also associated with the development of autoantibodies to insulin receptor, and to the presence of some hormonal/metabolic states e.g. Cushing syndrome. Acromegaly, gestational diabetes.
Physiological or psychological stress → insulin resistance.

8. Action of insulin: To maintain fuel homeostasis:-
1. Action of insulin on glucose transporters which facilitate glucose movement across cell membrane, e.g. GluT4 which play a role in ↓ blood glucose, is inserted into membrane of M and adipose tissue by insulin.
Defect in GluT2 →inhibits the transport of glucose → β cells → D.M.
2. Action of insulin on liver:
↑ Storage of glucose as glycogen by stimulation of glycogen synthesis, ↓ glycogenolysis, inhibition of gluconeogenesis, inhibition of ketogenesis.
3. Effect of insulin on muscles:
Promotes protein synthesis from A.A., stimulate glycogen synthesis, ↑ glucose transport → M cells, inducing glycogen synthase and inhibits phosphorylase.
4. Effect of insulin on adipose tissue:
Inhibit lipolysis in adipose tissue by inhibiting lipase enzyme → ↓ F.F.A., and glycerol, in insulin deficiency → ↑ FFA → liver → ketonbodies → ketoacidosis.

9. Diabetes mellitus (D.M.):
A heterogeneous group of disorders characterized by abnormalities in carbohydrate, protein and lipid metabolism, clinically manifested by hyperglycemia, glucosuria, hyperlipidemia, -ve nitrogen balance, ketonemia, ↑ thirst, polyphagia and polydypsia. The incidence of diabetes is growing rapidly
Types of D.M.:
Type-I, juvenile-onset D.M., insulin dependent D.M. (IDDM):
Affects individuals around puberty and childhood.
Absolute deficiency of insulin due to massive β cells necrosis due to autoimmune- mediated process triggered by viruses (mumps and coxackievirus B11. toxic chemicals.
Glucagon level ↑, non obese, ketosis. and the type 1 diabetic shows classic symptoms of insulin deficiency (polydipsia, polyphagia, polyuria, and weight loss).
Aim of Rx: exogenous insulin to avoid catabolic state ,hyperglycemia and ketoacidosis.

10. In a normal postabsorptive period, low basal levels of circulating insulin are maintained through constant β-cell secretion. This suppresses lipolysis, proteolysis, and glycogenolysis.
A burst of insulin secretion occurs within 2 minutes after ingesting a meal, in response to transient increases in the levels of circulating glucose and amino acids. This lasts for up to 15 minutes and is followed by the postprandial secretion of insulin.
However, those with type 1 diabetes can neither maintain a basal secretion level of insulin nor respond to variations in circulating fuels .
The development and progression of neuropathy, nephropathy, and retinopathy are directly related to the extent of glycemic control (measured as blood levels of glucose and/or hemoglobin A1c[HbA1c]) .
The rate of formation of HbA1c is proportional to the average blood glucose concentration over the previous 3 months. Therefore, HbA1c provides a measure of how well treatment has normalized blood glucose in diabetic patients.

11. Frequently occurs in patients over 35 years.
2. Type-II, non insulin dependent D.M. (NIDDM):
Frequently occurs in patients over 35 years.
The disease is influenced b genetic factors, aging, obesity, peripheral insulin resistance. No ketosis. the long-term clinical consequences can be just as devastating (for example, vascular complications and subsequent infection can lead to amputation of the lower limbs).
The pancreas retains some β cell function, variable insulin secretion insufficient to maintain glucose homeostasis. Type 2 diabetes is frequently accompanied by the lack of sensitivity of target organs to either endogenous or exogenous insulin. This resistance to insulin is considered to be a major cause of this type of diabetes.
Rx:The goal in treating type 2 diabetes is to maintain blood glucose concentrations within normal limits and to prevent the development of long-term complications of the disease , by oral hypoglycemic agent and/or insulin, diet, exercise & wt. reduction

12. 3. a-Type-III D.M., MODY (Maturity Onset Diabetes of the Young):
Autosomal dominant, non ketotic. Occur before 25 years, non obese patients, insulin resistance is absent.
b-drug induced
4. Type-IV D.M., gestational D.M:
Glucose intolerance during pregnancy, lead to fetal macrosomia (abnormally large body) and shoulder dystocia (difficult delivery), as well as neonatal hypoglycemia.
Rx: insulin, diet, exercise. Glyburide and metformin may be reasonably safe alternatives to insulin therapy

15. Sources of insulin: Animal insulin (bovine, porcine).
Human insulin: produced by recombinant DNA technology using special strains of E-coli or yeast (genetically altered to contain genes for human insulin).
Modification of human insulin (insulin analogues) e.g. Lispro, aspart and glulisine have faster onset and shorter duration of action than regular insulin because they form no aggregates on complex.
Absorbed rapid than animal insulin with shorter duration of action
Glargine, detimir → longer duration that level after injection.
Less immunogenic than bovine but not porcine.
*commercial insulin preparations differ in: purity, concentration, solubility, onset, duration and action.

16. Rapid-onset and ultra short-acting insulin preparation:
Conjugation of insulin + zinc or protamine or both, will convert the normally rapidly absorbed insulin to more prolong duration of action.
Rapid-onset and ultra short-acting insulin preparation:
Regular insulin:
Short acting, soluble, crystalline zinc insulin, rapidly lowers blood glucose.
Given subcutaneously, I.V. in emergencies.
Safe in pregnancy,

17. Has shorter duration of action.
2. Insulin Lispro.
3. Insulin aspart.
4. Insulin glulisine.
Insulin lispro differs from regular insulin in that lysine and proline at positions 28 and 29 in the B chain are reversed. This results in more rapid absorption after subcutaneous injection than is seen with regular insulin, given 15 minutes before meal or immediately following a meal .
Has shorter duration of action.
Peak level of Lispro min. after injection compared with min. for regular insulin.
Aspart and glulisine similar to Lispro.
Ultra short-acting due to their rapid onset and short duration of action, and offer more flexible Rx and lower the risk of hypoglycemia.

18. Usually not used alone but with longer acting insulin to assure proper glucose control.
Given S.C., I.V.
Insulin lispro, insulin aspart, and insulin glulisine may also be used in external insulin pumps .
Lispro preferred for external insulin pumps over regular because it doesn’t form hexamers.
{Precipitation of Lispro in infusion catheter → fluctuation in glucose control.}
-Regular insulin, insulin lispro, and insulin aspart are pregnancy category B, and insulin glulisine is pregnancy category C.

19. B. Intermediate-acting insulin preparation:
Isophane , NPH insulin suspension:
Neutral protamine Hagedorn(NPH) insulin is a suspension of crystalline zinc insulin combined at neutral pH with the positively charged poly-peptide protamine. (form less soluble complex → intermediate duration of action).
Given S.C. and never I.V.
Useful in Rx of all types of D.M. except ketoacidosis or emergency hyperglycemia.
It is used for basal control and is usually given along with rapid- or short-acting insulin for mealtime control.
A similar compound called neutral protamine lispro(NPL)insulin
has been prepared that is used only in combination with insulin lispro.

20. C. Prolonged-acting insulin preparation:
1. Ultralente insulin:
Poorly soluble insulin zinc crystals suspension.
Large particles → slowly dissolved → slow onset, long lasting hypoglycemia up to 35 hours.
2. Insulin glargine:
The isoelectric point of glargine is lower than that of human insulin → *precipitation at injection site → extend its action.
Slower than NPH in onset.
Has flat prolong hypoglycemic effect.
Must be given S.C.
3. Insulin detimir:
Has fatty acid side chain.
Associates with tissue-bound albumin at injection site, Slow dissociation from albumin results in long-acting properties similar to those of insulin glargine.
Neither insulin detemir nor insulin glargine should be mixed in the same syringe with other insulins, because doing so may alter the pharmacodynamic and pharmacokinetic properties.

21. Onset and duration of action of human insulin and insulin analogs
Onset and duration of action of human insulin and insulin analogs. NPH = Neutral Protamine Hagedorn

22. E. Aerosol preparation, oral spray
Others: Portable pen injectors → well accepted.
Continue S.C. insulin infusion devices {(CSII), insulin pumps} → manually programmable pump to deliver insulin replacement according to blood-glucose self- monitoring results.
Adverse reactions to insulin:
Hypoglycemia. Long-term diabetic patients commonly do not produce adequate amounts of the counter-regulatory hormones (glucagon ,cortisol , and growth hormone), which normally provide an effective defense against hypoglycemia.
lipodystrophy (less common with human insulin).
Allergic reaction. and local injection site reactions.
Wt .gain
Adjust the dose according to renal conditions.
Uses:
IDDM.
NIDDM uncontrolled by diet and hypoglycemic agent-oral type.
Gestational diabetes.
Infection, trauma and surgery and any complication of diabetes.
Rx of Hyperkalemia.

23. D. Insulin combination:
Various premixed combinations of human insulins, such as:
70-percent NPH insulin plus 30-percent regular insulin
50 percent of each of these, and
75-percent NPL insulin plus 25-percent insulin lispro, are also available

24. Standard treatment versus intensive treatment
For patients with diabetes mellitus who require insulin therapy, stan-dard treatment involves injection of insulin twice daily.
In contrast, intensive treatment seeks to normalize blood glucose through more frequent injections of insulin(three or more times daily in response to monitoring blood glucose levels).
The ADA recommends a target mean blood glucose level of 154 mg/dL or less (corresponding to a HbA1c of 7 percent or less) for patients with diabetes, and this is more likely to be achieved with intensive treatment.
The frequency of hypoglycemic episodes, coma, and seizures due to excessive insulin is higher with intensive treatment regimens.
Nonetheless, patients on intensive therapy show a significant reduction in such long-term complications of diabetes as retinopathy, nephropathy, and neuropathy compared to patients receiving standard care
Intensive therapy should generally not be recommended for patients with longstanding diabetes, significant microvascular complications, advanced age, and those with hypoglycemic unawareness.
Intensive therapy has not been shown to significantly reduce the macrovascular complications of diabetes.

25. SYNTHETIC AMYLIN ANALOG
Pramlintide is indicated as an adjunct to mealtime insulin therapy in patients with type 1 and type 2 diabetes.
Mechanism of action :-delays gastric emptying, decreases postprandial glucagon secretion, and improves satiety.
Pramlintide is administered by subcutaneous injection ,immediately prior to meals.
When pramlintide is initiated, the dose of rapid- or short-acting insulin should be decreased by 50 percent prior to meals to avoid a risk of severe hypoglycemia.
Pramlintide may not be mixed in the same syringe with any insulin preparation.
Adverse effects are mainly gastro-intestinal as nausea, anorexia, and vomiting
Pramlintide should not be given to patients with diabetic gastroparesis (delayed stomach emptying), cresol hypersensitivity, or a history of hypoglycemic unawareness.-

26. INCRETIN MIMETICS
Oral glucose results in a higher secretion of insulin than occurs when an equal load of glucose is given IV. This effect is referred to as the “incretin effect” and is markedly reduced in type 2 diabetes.
The incretin effect occurs because the gut releases incretin hormones, notably glucagon-like peptide-1 GLP-1 and glucose-dependent insulinotropic polypeptide, in response to a meal.
Incretin hormones are responsible for 60 to 70 percent of postprandial insulin secretion.
Exenatide and liraglutide are injectable incretin mimetics used for the treatment of patients with type 2 diabetes.
These agents may be used as adjunct therapy in patients who have failed to achieve adequate glycemic control on a sulfonylurea, metformin, a glitazone, or a combination thereof.

27. Mechanism of action
acting as GLP-1 receptor agonists.
improve glucose dependent insulin secretion
also slow gastric emptying time,
decrease food intake, decrease postprandial glucagon secretion, and
promote β-cell proliferation.
Consequently, weight gain and postprandial hyperglycemia are reduced, and HbA1c levels decline.

28. Pharmacokinetics and fate
Being polypeptides, exenatide and liraglutide must be administered
subcutaneously.
Liraglutide is highly protein bound and has a long half-life, allowing for once-daily dosing without regard to meals
Exenatideis eliminated mainly via glomerular filtration therefor, should be avoided in patients with severe renal impairment
has a much shorter half-life. Because of its short duration of action, it hould be injected twice daily within 60 minutes prior to morning and evening meals.
Adverse effects
consist of nausea, vomiting, diarrhea, and constipation.
Because of the peptide nature of incretin mimetics, patients may form antibodies to these agents.,but do not result in reduced efficacy of the drug or increased adverse effects.
Exenatide and liraglutide have been associated with pancreatitis. Patients should be advised to discontinue these agents and contact their healthcare provider immediately if they experience severe abdominal pain.
Liraglutide causes thyroid C-cell tumors in rodents. However, it is unknown if it causes these tumors or thyroid carcinoma in humans.