• Diabetes mellitus (DM) definition
• Pathophysiology of DM
• Symptoms of DM
• Types of diabetes mellitus
• Diabetic ketoacidosis
• Hyperosmolar (nonketotic hypergly-caemic) coma
• Oral hypoglycemic drugs
mellitus (DM) definition
• Diabetes mellitus (DM) It is a metabolic dis- order
characterized by hyperglycaemia, glycosuria and ketonaemia.
• A widespread pathological change is thickening of
capillary basement membrane, increase in vessel wall matrix and cellular
proliferation resulting in vascular complications like
• Lumen narrowing,
• Early atherosclerosis,
• Sclerosis of glomerular capillaries,
• Peripheral vascular insufficiency.
• Enhanced glycosylation of tissue proteins due to persistent
exposure to high glucose concentrations and the accumulation of larger quantities
of sorbitol (a reduced product of glucose) in tissues are believed to be
causative in the pathological changes of diabetes.
• Frequent Urination
• Blurry Vision
• Tingling in Hand and Feet
• Sudden Weight Loss
• Always Hungry
• Always Thirsty
• Wounds take time to heal
• Type 1 Insulin-dependent diabetes mellitus (IDDM)
/juvenile onset diabetes mellitus:
• There is β cell destruction in pancreatic islets; majority
of cases are autoimmune (type 1A) antibodies that destroy β cells are
detectable in blood.
• In all type 1 cases circulating insulin levels are low and
patients are more prone to ketosis.
• This type is less common and has a low degree of genetic
• Type II Noninsulin-dependent diabetes mellitus (NIDDM)/maturity
onset diabetes mellitus:
• Has a high degree of genetic predisposition; generally has
a late onset (past middle age). Over 90% cases of diabetes are type 2 DM.
• Cause: Reduced
sensitivity of peripheral tissues to insulin.
Type 2 Diabetes
• Insulin was discovered in 1921 by Banting and Best who
demonstrated the hypoglycaemic action of an extract of pancreas.
• Insulin is a two chain polypeptide having 51 amino acids
and MW about 6000. The A-chain has 21 while B-chain has 30 amino acids.
• There are minor differences between human, pork and beef
insulins: pork insulin is more homologous to human insulin than is beef
• Insulin is synthesized in the β cells of pancreatic islets
• Insulin facilitates glucose transport across cell
membrane; skeletal muscle and fat are highly sensitive.
• Insulin facilitates glycogen synthesis from glucose in
liver, muscle and fat by stimulating the enzyme glycogen synthase.
• Insulin inhibits gluconeogenesis (from pro- tein, FFA and
glycerol) in liver.
• Insulin inhibits lipolysis in adipose tissue and favours
• In diabetes increased amount of fat is broken down due to
unchecked action of lipolytic hormones (glucagon) → increased FFA and glycerol
in blood → taken up by liver to produce acetyl-CoA.
• Normally acetyl-CoA is resynthesized to fatty acids and
triglycerides, but this process is reduced in diabetics and acetyl CoA is
diverted to produce ketone bodies (acetone, acetoacetate,β-hydroxy-butyrate).
• Insulin facilitates AA entry and their synthesis into
proteins, as well as inhibits protein breakdown in muscle and most other cells.
Insulin deficiency leads to protein breakdown → AAs are released
in blood → taken up by liver and converted to Glucose.
insulin producing hypoglycaemia
• Insulin is distributed only extracellularly.
• It is a peptide; gets degraded in the g.i.t. if given
• Injected insulin or that released from pancreas is
metabolized primarily in liver and to a smaller extent in kidney and muscles.
• The plasma t½ is 5–9 min.
• The older commercial preparations were produced from beef
and pork pancreas.
• They contained ~1%(10,000 ppm) of other proteins
(proinsulin, other polypeptides, pancreatic proteins, insulin derivatives,
etc.) which were potentially antigenic.
• They are no longer produced and have been totally replaced
by highly purified pork/beef insulins/recombinant human insulins/insulin
purified insulin preparations
• In the 1970s improved purification techniques like gel
filtration and ion-exchange chromatography were applied to produce
‘monocomponent (MC)’ insulins which contain <10 ppm proinsulin.
• They are less antigenic.
• It is a buffered neutral pH solution of unmodified insulin
stabilized by a small amount of zinc.
• At the concentration of the injectable solution, the
insulin molecules self-aggregate to form hexamers around zinc ions.
• After s.c. injection, insulin monomers are released
gradually by dilution, so that absorption occurs slowly.
• Peak action is produced only after 2–3 hours and action
continues upto 6–8 hours.
• Two types of insulin-zinc suspensions have been produced.
• The one with large particles is crystalline and
practically insoluble in water (ultralente). It is long-acting.
• The other has smaller particles and is amorphous
(semilente), is short- acting.
• Their 7:3 ratio mixture is called ‘Lente insulin’ and is
Protamine Hagedorn or NPH) insulin
• Protamine is added in a quantity just sufficient to
complex all insulin molecules;
• Neither of the two is present in free form and pH is
• On s.c. injection, the complex dissociates slowly to yield
an intermediate duration of action.
• 1. Highly purified (monocomponent) pork regular insulin:
ACTRAPID MC, RAPIDICA 40U/ml inj.
• 2. Highly purified (MC) pork lente insulin: LENTARD,
MONOTARD MC, LENTINSULIN-HPI, ZINULIN 40 U/ml.
• 3. Highly purified (MC) pork isophane (NPH) insulin:
INSULATARD 40 U/ml inj.
• In the 1980s, the human insulins (having the same amino
acid sequence as human insulin) were produced by recombinant DNA technology in
Escherichia coli—‘proinsulin recombinant bacterial’ (prb) and in
yeast—‘precursor yeast recombinant’ (pyr), or by ‘enzymatic modification of
porcine insulin’ (emp).
Human insulins available
• 1. HUMULIN R: Human regular insulin; 40 U/ml, 100 U/ml.
• 2. HUMULIN-L: Human lente insulin; 40 U/ml, 100 U/ml.
• 3. HUMULIN-N: Human isophane insulin 40 U/ml.
• In the USA pork and beef insulins are no longer
manufactured, but they are still available in U.K., India and some European
• In Britain now > 90% diabetics who use insulin are
taking human insulins or insulin analogues.
• In India also human insulins and analogues are commonly
used, except for considerations of cost.
• can occur in any diabetic following inadvertent injection
of large dose, by missing a meal after injection or by performing vigorous
• The symptoms can be divided into those due to counter-regulatory
sympathetic stimulation—sweating, palpitation, tremor;
• And those due to deprivation of the brain of its essential
nutrient glucose (neuroglucopenic symptoms)—dizziness, headache, behavioural
Glucose must be given orally or i.v. (for severe cases)—reverses the symptoms
• Lipodystrophy of the subcutaneous fat around the injection
site may occur if the same site is injected repeatedly. This is rare with the
• This is due to contaminating proteins, and is very rare
with human/highly purified insulins. Urticaria, angioedema and anaphylaxis are
• Diabetes mellitus
• Insulin is effective in all forms of diabetes mellitus and
is a must for type 1 cases, and gestational diabetes.
• Many type 2 cases can be controlled by diet, reduction in
body weight and appropriate exercise supplemented, if required, by oral
requirment in Type 2 DM
• Insulin is needed by patients with type 2 DM patient when:
• Not controlled by diet and exercise or when these are not
• Primary or secondary failure of oral hypoglycaemics or
when these drugs are not tolerated.
• Underweight patients.
• Temporarily to tide over infections, trauma, surgery,
pregnancy. In the perioperative period and during labour, monitored i.v.
insulin infusion is preferable.
• Any complication of diabetes, e.g. ketoacidosis,
nonketotic hyperosmolar coma, gangrene of extremities.
• Most type 1 patients require 0.4–0.8 U/kg/day.
• In type 2 patients, insulin dose varies (0.2–1.6U/kg/day)
with the severity of diabetes and body weight:
• Obese patients require proportionately higher doses due to
relative insulin resistance.
• Generally occurs in insulin dependent diabetics. (Type 1
• Precipitating cause is infection; others are trauma,
stroke, pancreatitis, stressful conditions and inadequate doses of insulin.
Treatment of DKA
• Intravenous fluids
• KCl: When insulin therapy is instituted ketosis subsides
and K+ is driven back intracellularly— dangerous hypokalemia can occur.
• Sodium bicarbonate
(nonketotic hypergly-caemic) coma
• occurs in type 2 DM.
• Uncontrolled glycosuria of DM produces diuresis resulting
in dehydration and haemoconcentration over several days → urine output is
finally reduced and glucose accumulates in blood rapidly to > 800 mg/dl,
plasma osmolarity is > 350 mOsm/ L → coma, and death can occur
Hyperosmolar coma management
• The general principles of treatment are the same as for
ketoacidotic coma, except that faster fluid replacement is to be instituted and
alkali is usually not required.
• These patients are prone to thrombosis (due to
hyperviscosity and sluggish circulation), prophylactic heparin therapy is
• These drugs lower blood glucose levels and are effective
• The chief drawback of insulin is—it must be given by injection.
Classification of Oral hypoglycemic
Enhance Insulin secretion
• First generation: Tolbutamide
• Second generation: Glibenclamide, Glipizide,
• Repaglinide, Nateglinide
peptide-1 (GLP-1) receptor agonists (Injectable drugs)
• Exenatide, Liraglutide
peptidase-4 (DPP-4) inhibitors
• Sitagliptin, Vildagliptin.
Overcome Insulin resistance
(PPAR γ activator)
Miscellaneous antidiabetic drugs
• α-Glucosidase inhibitors
• Acarbose, Miglitol, Voglibose
• Sodium-glucose cotransport-2 (SGLT-2) Inhibitor:
enhance insulin secretion
(KATP Channel blockers)
• Mechanism of action: Sulfonylureas provoke a brisk release
of insulin from pancreas.
Adverse effects of SU
analogues (KATP Channel blockers)
• MOA: release of
insulin from pancreas.
• They induce rapid onset short lasting insulin release.
• Administered before each major meal to control post
peptide-1 (GLP-1) receptor agonists
• GLP-1 is an important incretin released from the gut in
response to ingested glucose.
• It induces insulin release from pancreatic β cells,
inhibits glucagon release from α cells, slows gastric emptying and suppresses
• Drugs available: Exenatide, Liraglutide(Victoza)
peptidase-4 (DPP-4) inhibitors
• DPP-4 in rapid degradation of endogenous GLP-1, orally
active inhibitors of DPP-4 have been developed as indirectly acting insulin
• Sitagliptin, Vildagliptin, Saxagliptin
overcome insulin resistance
• Phenformin higher risk of lactic acidosis banned in India
Enhances insulin-mediated glucose uptake and disposal in skeletal muscle and
• Adverse effects:
Lactic acidosis, g.i. intolerance.
• MOA: Glitazones
tend to reverse insulin resistance by enhancing GLUT4 expression and
• Entry of glucose into muscle and fat is improved.
• (Rosiglitazone, is banned in India due to unacceptable
increase in risk of myocardial infarction, CHF, stroke and death.)
α Glucosidase inhibitors
• Acarbose: inhibits α-glucosidases, the final enzymes for
the digestion of carbohydrates in the brush border of small intestine mucosa.
• Flatulence, abdominal discomfort and loose stool are
produced in about 50% patients due to fermentation of unabsorbed carbohydrates.
co-transport-2 (SGLT-2) Inhibitor
• Practically all the glucose filtered at the glomerulus is
reabsorbed in the proximal tubules.
• The major transporter which accomplishes this is SGLT-2,
• Inhibition of SGLT-2 induces glucosuria and lowers blood
glucose in type 2 DM, as well as causes weight loss.