Insulin, Oral Hypoglycemics Drugs and Glucagon

 Chapter -19 

Insulin, Oral Hypoglycemics Drugs and Glucagon

• Diabetes mellitus (DM) It is a metabolic disorder characterized by hyperglycemia, glycosuria, hyperlipemia, negative nitrogen balance and sometimes ketonemia. 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, retinopathy, neuropathy and peripheral vascular insufficiency.

• Enhanced nonenzymatic 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. The concentration of glycosylated hemoglobin (HbA1c) is taken as an index of protein glycosylation: it reflects the state of glycaemia over the preceding 2–3 months.

• Two major types of diabetes mellitus are:

• Type I 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, but some are idiopathic (type 1B)—no β cell antibody is found. In all type 1 cases circulating insulin levels are low or very low, and patients are more prone to ketosis. This type is less common and has a low degree of genetic predisposition.

Type II Noninsulin-dependent diabetes mellitus (NIDDM), maturity onset diabetes mellitus: There is no loss or moderate reduction in β cell mass; insulin in circulation is low, normal or even high, no anti-β-cell antibody is demonstrable; has a high degree of genetic predisposition; generally, has a late onset (past middle age). Over 90% cases are type 2 DM. Causes may be:

• Abnormality in glucan-receptor of β cells so that they respond at higher glucose concentration or relative β cell deficiency. 

• Reduced sensitivity of peripheral tissues to insulin: reduction in number of insulins receptors, ‘down regulation’ of insulin receptors. Many hypertensives are hyperinsulinemia, but normoglycemic; exhibit insulin resistance associated with dyslipidemias (metabolic syndrome). Hyperinsulinemia per se has been implicated in causing angiopathy. 

• Excess of hyperglycemic hormones (glucagon, etc.)/obesity: cause relative insulin deficiency—the β cells lag behind.

INSULIN

Insulin was discovered in 1921 by Banting and Best who demonstrated the hypoglycemic action of an extract of pancreas prepared after degeneration of the exocrine part due to ligation pancreatic duct. It was first obtained in pure crystalline form in 1926 and the chemical structure was fully worked out in 1956 by Sanger. 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:

Thus, pork insulin is more homologous to human insulin than is beef insulin. The A and B chains are held together by two disulfide bonds.

Insulin is synthesized in the β cells of pancreatic islets as a single chain peptide PR proinsulin (110 AA) from which 24 AAs are first removed to produce Proinsulin (Fig. 19.1). The connecting or ‘C’ peptide (35 AA) is split off by proteolysis in Golgi apparatus; both insulin and C peptide are stored in granules within the cell. The C peptide is secreted in the blood along with insulin.

Assay Insulin is Bio assayed by measuring blood sugar depression in rabbits (1 U reduces blood glucose of a fasting rabbit to 45 mg/dl) or by its potency to induce hypoglycemic convulsions in mice. 1 mg of the International Standard of insulin = 28 units. With the availability of pure preparations, it can now be assayed chemically also. Plasma insulin can be measured by radioimmunoassay or enzyme immunoassay.

Regulation of insulin secretion

• Under basal condition ~1U insulin is secreted per hour by human pancreas. Much larger quantity is secreted after every meal. Secretion of insulin from β cells is regulated by chemical, hormonal and neural mechanisms.

• Chemical The β cells have a glucose sensing mechanism dependent on entry of glucose into

• β cells (through the aegis of a glucose transporter GLUT2) and its phosphorylation by glucokinase. Glucose entry and activation of the glucometer indirectly inhibits the ATP-sensitive K+ channel resulting in partial depolarization of the β cells. This increases intracellular Ca2+ availability (due to increased influx, decreased efflux and release from intracellular stores) → exocytotic release of insulin storing granules. Other nutrients that can evoke insulin release are—amino acids, fatty acids and ketone bodies, but glucose is the principal regulator, and it stimulates synthesis of insulin as well. Glucose induces a brief pulse of insulin output within 2 min (first phase) followed by a delayed but more sustained second phase of insulin release.

• Glucose and other nutrients are more effective in invoking insulin release when given orally than i.v. They generate chemical signals ‘incretins’ from the gut which act on β cells in the pancreas to cause anticipatory release of insulin. The incretins involved are glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), vasoactive intestinal peptide (VIP), pancreozymin cholecystokinin, etc.; but different incretin may mediate signal from different nutrient. Glucagon and some of these peptides enhance insulin release by increasing cAMP formation in the β cells.

• Hormonal A number of hormones, e.g. growth hormone, corticosteroids, thyroxine modify insulin release in response to glucose. PGE has been shown to inhibit insulin release. More important are the intra-islet paracrine interactions between the hormones produced by different types of islet cells. The β cells constitute the core of the islets and are the most abundant cell type. The α cells, comprising 25% of the islet cell mass, surround the core and secrete glucagon. The D cells (5–10%) elaborating somatostatin are interspersed between the α cells. There are some PP (or F) cells (pancreatic polypeptide containing) also.

1. Somatostatin inhibits release of both insulin and glucagon. 
2. Glucagon evokes release of insulin as well as somatostatin. 
3. Insulin inhibits glucagon secretion.

The three hormones released from closely situated cells influence each other’s secretion and

appear to provide fine tuning of their output in response to metabolic needs

Neural The islets are richly supplied by sympathetic and vagal nerves.

• Adrenergic α2 receptor activation decreases insulin release (predominant) by inhibiting β cell adenylyl cyclase. 

• Adrenergic β2 stimulation increases insulin release (less prominent) by stimulating β cell adenylyl cyclase. 

• Cholinergic—muscarinic activation by Ach or vagal stimulation causes insulin secretion through IP3/DAG-increased intracellular Ca2+ in the β cells.

These neural influences appear to govern both basal as well as evoked insulin secretion, because the respective blocking agents have effects opposite to that mentioned above. The primary central site of regulation of insulin secretion is in the hypothalamus: stimulation of ventrolateral nuclei evokes insulin release, whereas stimulation of ventromedial nuclei has the opposite effect.

ACTIONS OF INSULIN

The overall effects of insulin are to Favour storage of fuel. The actions of insulin and the results of its deficiency can be summarized as:

• Insulin facilitates glucose transport across cell membrane; skeletal muscle and fat are highly sensitive. The availability of glucose intracell- larky is the limiting factor for its utilization in these and some other tissues. However, glucose entry in liver, brain, RBC, WBC and renal medullary cells is largely independent of insulin. Ketoacidosis interferes with glucose utilization by brain → diabetic coma. Muscular activity induces glucose entry in muscle cells without the need for insulin. As such, exercise has insulin sparing effect.

• The intracellular pool of vesicles containing glucose transporter glycoproteins GLUT4 (insulin activated) and GLUT1 is in dynamic equilibrium with the GLUT vesicles inserted into the membrane. This equilibrium is regulated by insulin to Favour translocation to the membrane. Moreover, on a long-term basis, synthesis of GLUT4 is upregulated by insulin.

• The first step in intracellular utilization of glucose is its phosphorylation to form glucose-6- phosphate. This is enhanced by insulin through increased production of glucokinase. Insulin facilitates glycogen synthesis from glucose in liver, muscle and fat by stimulating the enzyme glycogen synthase. It also inhibits phosphorylase → decreased glycogenolysis in liver.

• Insulin inhibits gluconeogenesis (from protein, FFA and glycerol) in liver by gene mediated decreased synthesis of phosphonyl pyruvate carboxin's. In insulin deficiency, proteins and amino acids are funneled from peripheral tissues to liver where these are converted to carbohydrate and urea. Thus, in diabetes there is underutilization and over production of glucose → hyperglycemia → glycosuria.

• Insulin inhibits lipolysis in adipose tissue and Favours triglyceride synthesis. In diabetes increased amount of fat is broken down due to unchecked action of lipolytic hormones (glucagon, Ard, thyroxine, etc.) → 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). The ketone bodies are released in blood—partly used up by muscle and heart as energy source, but when their capacity is exceeded, ketonemia and ketonuria result.

• Insulin enhances transcription of vascular endothelial lipoprotein lipase and thus increases clearance of VLDL and chylomicrons.

• 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 pyruvate, glucose and urea. The excess urea produced is excreted in urine resulting in negative nitrogen balance. Thus, catabolism takes the upper hand over anabolism in the diabetic state.

Most of the above metabolic actions of insulin are exerted within seconds or minutes and are called the rapid actions. Others involving DNA mediated synthesis of glucose transporter and some enzymes of amino acid metabolism have also been    

latency of few hours—the intermediate actions. In addition insulin exerts major long-term effects on multiplication and differentiation of cells.

• Mechanism of action Insulin acts on specific receptors located on the cell membrane of practically every cell, but their density depends on the cell type: liver and fat cells are very rich. The insulin receptor is a heterotetrametric glycoprotein consisting of 2 extracellular α and 2 transmembrane β subunits linked together by disulfide bonds. It is oriented across the cell membrane as a heterodimer (Fig. 19.3). The α subunits carry insulin binding sites, while the β subunits have tyrosine protein kinase activity.

• Binding of insulin to α subunits induces aggregation and internalization of the receptor along with the bound insulin molecules. This activates tyrosine kinase activity of the β subunits → pairs of β subunits phosphorylate tyrosine residues on each other → expose the catalytic site to phosphorylate tyrosine residues of Insulin Receptor Substrate proteins (IRS1, IRS2, etc). In turn, a cascade of phosphorylation and dephosphorylation reactions is set into motion resulting in stimulation or inhibition of enzymes involved in the rapid metabolic actions of insulin.

• Certain second messengers like phosphatidyl inositol trisphosphate (PIP3) which are generated through activation of a specific PI3-kinase also mediate the action of insulin on metabolic enzymes.    

• Insulin stimulates glucose transport across cell membrane by ATP dependent translocation of glucose transporter GLUT4 and GLUT1 to the plasma membrane as well as by increasing its activity. Over a period of time it also promotes expression of the genes directing synthesis of GLUT4. Genes for a large number of enzymes and carriers have been shown to be regulated by insulin primarily through MAP kinases. Activation of transcription factors also promotes proliferation and differentiation of specific cells.

• The internalized receptor-insulin complex is either degraded intracellularly or returned back to the surface from where the insulin is released extracellularly. The relative preponderance of these two processes differs among different tissues: maximum degradation occurs in liver, least in vascular endothelium.

 Fate of insulin is distributed only extracellularly. It is a peptide; gets degraded in the g.i.t. if given orally. Injected insulin or that released from pancreas is metabolized primarily in liver and to a smaller extent in kidney and muscles. Nearly half of the insulin entering portal vein from pancreas is inactivated in the first passage through liver. Thus, normally liver is exposed to a much higher concentration (4–8 fold) of insulin than are other tissues. As noted above, degradation of insulin after receptor mediated internalization occurs to variable extents in most target cells. During biotransformation the disulfide bonds are reduced A and B chains are separated. These are further broken down to the constituent amino acids. The plasma t½ is 5–9 min.

Conventional preparations of insulin.

The conventional commercial preparations are produced from beef and pork pancreas. They contain ~1% (10,000 ppm) of other proteins (proinsulin, other polypeptides, pancreatic protein   insulin derivatives, etc.) which are potentially antigenic. In the developed countries, these have been totally replaced by highly purified pork insulins/recombinant human insulins/insulin analogues. However, because of low cost, conventional preparations are still used in India and many developing countries. The types of insulin preparations are tabulated in

• Regular (soluble) insulin: It is a buffered 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 sac injection, insulin monomers are released gradually by dilution, so that absorption occurs slowly. Peak action is produced only after 2–4 hours and action continue up to 6–8 hours. The absorption pattern is also affected by dose; higher doses act longer. When injected sac just before a meal, this pattern often creates a mismatch between need and availability of insulin to result in early postprandial hyperglycemia and late postprandial hypoglycemia. Regular insulin injected sac is also not suitable for providing a low constant basal level of action in the interdigitate period.

• To overcome the above problems, some long acting ‘modified’ or ‘retard’ preparations of insulin were soon developed. Recently, both rapidly acting as well as peak less and long-acting insulin analogues have become available. However, after i.v. injection, the hexametric regular insulin dissociates rapidly to produce prompt action.

• For obtaining retard preparations, insulin is rendered insoluble either by complexing it with protamine (a small molecular basic protein) or by precipitating it with excess zinc and increasing the particle size.

• Lente insulin (Insulin-zinc suspension): Two types of insulin-zinc suspensions have been produced. The one with large particles is crystalline and practically insoluble in water (ultra-Lente or ‘extended insulin zinc suspension’). It is long acting. The other has smaller particles and is amorphous (semilength or ‘prompt insulin zinc suspension’), is short-acting. Their 7:3 ratio mixture is called ‘Lente insulin’ and is intermediate-acting.

• Isophane (Neutral 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 neutral. On s.c. injection, the complex dissociates slowly to yield an intermediate duration of action.

• Protamine zinc insulin (PZI): It contains excess of protamine, so that the complexed insulin is released more slowly at the site of s.c. injection and a long-acting preparation results. It is rarely used now..

1. Regular insulin: SOLUBLE INSULIN 40 U/ml, 100 U/ml, for s.c. or i.v. injection. 
2. Lente insulin (insulin zinc suspension) 7:3: LENTE INSULIN 40 U/ml for s.c. inj. 
3. Neutral protamine Hagedorn (NPH) insulin: ISOPHANE (NPH) INSULIN 40 U/ml for s.c. inj. 
4. Protamine zinc insulin: PROTAMINE ZINC INSULIN 40 U/ml for s.c. inj.

Highly purified insulin preparations

In the 1970s improved purification techniques were applied to produce highly purified and practically nonantigenic insulins. Pork insulin, being more homologous to human insulin, is less immunogenic and is used. Gel filtration reduces proinsulin content to 50–200 ppm, but pancreatic peptides and insulin derivates remain; the preparation is called ‘single peak insulin’. It still has significant immunogenicity. Further purification by ion-exchange chromatography removes most contaminants and reduces proinsulin to <10 ppm. These preparations are termed ‘Highly purified’ or ‘Mono component (MC) insulins. Immunogenicity of pork MC insulins is similar to that of human insulins. Moreover, MC insulins are more stable, cause less insulin resistance or injection site lipodystrophy.

• Highly purified (Mono component) pork regular insulin: ACTRAPID MC, RAPIDICA 40 U/ml inj. 

• Highly purified (MC) pork Lente insulin: LENTARD, MONOTARD MC, LENTINSULIN-HPI, ZINULIN 40 U/ml 

• Highly purified (MC) pork isophane (NPH) insulin: INSULATARD 40 U/ml inj. 

• Mixture of highly purified pork regular insulin (30%) and isophane insulin (70%): RAPIMIX, MIXTARD 40 U/ml inj.

Human insulins 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’ (orb) and in yeast— ‘precursor yeast recombinant’ (pry), or by ‘enzymatic modification of porcine insulin (emp).

• HUMAN ACTRAPID: Human regular insulin; 40 U/ ml, 100 U/ml, ACTRAPID HM PENFIL 100 U/ml pen inj., WOSULIN-R 40 U/ml inj vial and 100 U/ml pen injector cartridge. 

• HUMAN MONOTRAD: Human Lente insulin; 40 U/ ml, 100 U/ml. 

• HUMAN INSULATARD, HUMINSULIN-N: Human isophane insulin 40 U/ml. WOSULIN-N 40 U/ml inj. vial and 100 U/ml pen injector cartridge.

• HUMAN ACTRAPHANE, HUMINSULIN 30/70, HUMAN MIXTARD: Human soluble insulin (30%) and isophane insulin (70%), 40 U/ml. WOSULIN 30/70: 40 U/ml vial and 100 U/ml cartridge. 

• ACTRAPHANE HM PENFIL: Human soluble insulin 30% + isophane insulin 70% 100 U/ml pen injector. 

• INSUMAN 50/50: Human soluble insulin 50% + isophane insulin 50% 40 U/ml in; WOSULIN 50/50 40 U/ml vial, 100 U/ml cartridge. 

In the USA and Europe, the use of human insulins has rapidly overtaken that of purified animal insulins: in Britain now > 90% diabetics who use insulin are taking human insulins or insulin analogues. Human insulin is more water soluble as well as hydrophobic than porcine or bovine insulin. It has a slightly more rapid sac absorption, earlier and more defined peak and slightly shorter duration of action.

The allegation that human insulin produces more hypoglycemic unawareness has not been substantiated. However, after prolonged treatment, irrespective of the type of insulin, many diabetics develop relative hypoglycemic unawareness/change in symptoms, because of autonomic neuropathy, changes in perception/attitude and other factors. The cost of human insulin now is the same as that of pork MC insulin

Superiority of human insulin over pork MC insulin has not been demonstrated. Though new patients may be started on human insulins, the only indication for transfer from purified pork to human insulin is allergy to pork insulin. It is unwise to transfer stabilized patients from one to another species insulin without good reason.

Though it is desirable to employ human/ highly purified pork insulin in all diabetics, in developing countries conventional insulin preparations are still used for economic reasons. Human/highly purified insulins are specially indicated in the following situations:

• Insulin resistance: especially when due to large amounts of insulin-binding antibodies. 

• Allergy to conventional preparations. 

• Injection site lipodystrophy: changeover causes resolution of the lesions. 

• Short-term use of insulin in diabetics who are otherwise stabilized on diet and exercise with/without oral hypoglycemics', e.g., to takeover surgery, trauma, infections, ketoacidosis, etc. 

• During pregnancy.

Insulin analogues

• Using recombinant DNA technology, analogues of insulin have been produced with modified pharmacokinetics on sac injection, but similar pharmacodynamic effects. Greater stability and consistency are the other advantages.

• Insulin lispro: Produced by reversing proline and lysine at the carboxy terminus B 28 and B 29 positions, it forms very weak hexamers that dissociate rapidly after sac injection resulting in a quick and more defined peak as well as shorter duration of action. Unlike regular insulin, it needs to be injected immediately before or even after the meal, so that dose can be altered according to the quantity of food consumed. A better control of meal-time glycaemia and a lower incidence of late post-prandial hypo glycaemia have been obtained. Using a regimen of 2–3 daily meal-time insulin lispro injections, a slightly greater reduction in HbA1c compared to regular insulin has been reported. Fewer hypoglycemic episodes occurred. HUMALOG 100 U/ml inj.

• Insulin asp art: The proline at B 28 of human insulin is replaced by aspartic acid. This change reduces the tendency for self-aggregation, and a time-action profile similar to insulin lispro is obtained. It more closely mimics the physiological insulin release pattern after a meal, with the same advantages as above.

• NOVOLOG, NOVORAPID 100 U/ml inj. 

• Insulin gallisin: Another rapidly acting insulin analogue with lysine replacing asparagine at B 23 and glutamic acid replacing lysine at B 29. Properties and advantages are similar to insulin lispro

• Insulin glargine: This long-acting biosynthetic insulin has 2 additional arginine residues at the carboxy terminus of B chain and glycine replaces asparagine at A 21. It remains soluble at pH4 of the formulation, but precipitates at neutral pH encountered on sac injection. A depot is created from which monomeric insulin dissociates slowly to enter the circulation. Onset of action is delayed, but relatively low blood levels of insulin are maintained for up to 24 hours. A smooth ‘peak less’ effect is obtained. Thus, it is suitable for once daily injection to provide background insulin action. Fasting and interdigitate blood glucose levels are effectively lowered irrespective of time of the day when injected or the site of such injection. Lower incidence of night-time hypoglycemic episodes compared to isophane insulin has been reported. However, it does not control meal-time glycaemia, for which a rapid acting insulin or an oral hypoglycemic is used concurrently. Because of acidic pH, it cannot be mixed with any other insulin preparation; must be injected separately.

• be injected separately. LANTUS OPTISET 100 U/ml in 5 ml vial and 3 ml prefilled pen injector.

REACTIONS TO INSULIN

• Hypoglycemia This is the most frequent and potentially the most serious reaction. It is commonly seen in patients of ‘labile’ diabetes in whom insulin requirement fluctuates unpredictably. Hypoglycemia can occur in any diabetic following inadvertent injection of large doses, by missing a meal or by performing vigorous exercise. The symptoms can be divided into those due to counter-regulatory sympathetic stimulation— sweating, anxiety, palpitation, tremor; and those due to deprivation of the brain of its essential nutrient glucose (neuroglycopenic symptoms) — dizziness, headache, behavioral changes, visual disturbances, hunger, fatigue, weakness, muscular incoordination and sometimes fall in BP. Generally, the reflex sympathetic symptoms occur before the neuroglycopenic, but the warning symptoms of hypoglycemia differ from patient to patient and also depend on the rate of fall in blood glucose level. After long-term treatment about 30% patients lose adrenergic symptoms. Diabetic neuropathy can abolish the autonomic symptoms. Hypoglycemic unawareness tends to develop in patients who experience frequent episodes of hypoglycemia.

• Finally, when blood glucose falls further (to < 40 mg/dl) mental confusion, abnormal behavior, seizures and coma occur. Irreversible neurological deficits are the sequelae of prolonged hypoglycemia.

• Treatment Glucose must be given orally or i.e. (for severe cases)—reverses the symptoms rapidly. Glucagon 0.5–1 mg i.e. or Adr 0.2 mg sac (less desirable) may be given as an expedient measure in patients who are not able to take sugar orally and injectable glucose is not available.

• Local reactions Swelling, erythema and stinging sometimes occur especially in the beginning. Lipodystrophy occurs at injection sites after long usage. This is not seen with newer preparations—which may even facilitate reversal of lipoatrophy when injected at the same sites.

• Allergy This is infrequent; is due to contaminating proteins; very rare with human/highly purified insulins. Urticaria, angioedema and anaphylaxis are the manifestations.

• Edema Some patients develop short-lived dependent edema (due to Na+ retention) when insulin therapy is started.

Drug interactions

• β adrenergic blockers prolong hypoglycemia by inhibiting compensatory mechanisms operating through β2 receptors (β1 selective agents are less liable). Warning signs of hypoglycemia like palpitation, tremor and anxiety are masked. Rise in BP can occur due to unopposed α action of released Ard. 

• Thiazides, furosemide, corticosteroids, oral contraceptives, salbutamol, nifedipine tend to raise blood sugar and reduce effectiveness of insulin. 

• Acute ingestion of alcohol can precipitate hypoglycemia by depleting hepatic glycogen. 4. Salicylates, lithium and theophylline may also accentuate hypoglycemia by enhancing insulin secretion and peripheral glucose utilization.

USES OF INSULIN

Diabetes mellitus the purpose of therapy in diabetes mellitus is to restore metabolism to normal, avoid symptoms due to hyperglycemia and glucosuria, prevent short-term complications (infection, ketoacidosis, etc.) and long-term sequalae (cardiovascular, retinal, neurological, renal, etc.)

Insulin is effective in all forms of diabetes mellitus and is a must for type 1 cases, as well as for post pancreatectomy diabetes and gestational diabetes. Many types 2 cases can be controlled by diet, reduction in body weight and appropriate exercise. Insulin is needed by such patients when:

• Not controlled by diet and exercise or when these are not practicable. 

• Primary or secondary failure of oral hypoglycemics or when these drugs are not tolerated. 

• Underweight patients. 

• Temporarily to tide over infections, trauma, surgery, pregnancy. In the perioperative period and during labor, monitored i.e. insulin infusion is preferable. 

• Any complication of diabetes, e.g., ketoacidosis, nonketotic hyperosmolar coma, gangrene of extremities. 

When instituted, insulin therapy is generally started with regular insulin given sac before each major meal. The requirement is assessed by testing urine or blood glucose levels (glucose oxidase-based spot tests and glucometers are available). Most type 1 patients require 0.4–0.8 U/kg/day. In type 2 patients, insulin dose varies (0.2–1.6 U/ kg/day) with the severity of diabetes and body weight: obese patients require proportionately higher doses due to relative insulin resistance. A suitable regimen for each patient is then devised by including modified insulin preparations.

Any satisfactory regimen should provide basal control by inhibiting hepatic glucose output, as well as supply extra amount to meet postprandial needs for disposal of absorbed glucose and amino acids. Often mixtures of regular and Lente/isophane insulins are used. The total daily dose of a 30:70 mixture of regular and NPH insulin is usually split into two (split-mixed regimen) and injected sac before breakfast and before dinner. Several variables viz. site and depth of sac injection, posture, regional muscular activity, injected volume, type of insulin can alter the rate of absorption of sac injected insulin and can create mismatch between the actual requirement (high after meals, low at night) and the attained insulin levels

Another preferred regimen is to give a long-acting insulin (glargine) once daily either before breakfast or before bedtime for basal coverage along with 2–3 mealtime injections of a rapid acting preparation (insulin lispro or apart). Such intensive regimens have the objective of achieving round-the-clock euglycemia. The large multicentric diabetes control and complications trial (DCCT) among type 1 patients has established that intensive insulin therapy markedly reduces the occurrence of primary diabetic retinopathy, neuropathy, nephropathy and slows progression of these complications in those who already have them in comparison to conventional regimens which attain only intermittent euglycemia. Thus, the risk of macrovascular disease appears to be related to the glycaemia control. The UK prospective diabetes study (UK PDS, 1998) has extended these observations to type 2 DM patients as well. Since the basis of pathological changes in both type 1 and type 2 DM is accumulation of glycosylated proteins and sorbitol in tissues as a result of exposure to high glucose concentrations, tight glycaemia control can delay end-organ damage in all diabetic subjects

However, regimens attempting near normoglycemia are associated with higher incidence of severe hypoglycemic episodes. Moreover, injected insulin fails to reproduce the normal pattern of increased insulin secretion in response to each meal, and liver is exposed to the same concentration of insulin as other tissues while normally liver receives much higher concentration. As such, the overall desirability and practicability of intensive insulin therapy has to be determined in individual patients. Intensive insulin therapy is best avoided in young children (risk of hypoglycemic brain damage) and in the elderly (more prone to hypoglycemia and its serious consequences).

Diabetic ketoacidosis (Diabetic coma) Ketoacidosis of different grades generally occurs in insulin dependent diabetics. It is infrequent in type 2 DM. The most common precipitating cause is infection; others are trauma, stroke, pancreatitis, stressful conditions and inadequate doses of insulin.

The development of cardinal features of diabetic's ketoacidosis is outlined in Fig. 19.4. Patients may present with varying severity. Typically, they are dehydrated, hyperventilating and have impaired consciousness. The principles of treatment remain the same, irrespective of severity, only the vigour with which therapy is instituted is varied.

• Insulin Regular insulin is used to rapidly correct the metabolic abnormalities. A bolus dose of 0.1–0.2 U/kg i.e., is followed by 0.1 U/kg/hr. infusion; the rate is doubled if no significant fall in blood glucose occurs in 2 hr. Fall in blood glucose level by 10% per hour can be considered adequate response Usually, within 4–6 hours blood glucose reaches 300 mg/dl. Then the rate of infusion is reduced to 2–3 U/hr. This is maintained till the patient becomes fully conscious and routine therapy with sac insulin is instituted.

• Intravenous fluids It is vital to correct dehydration. Normal saline is infused i.e., initially at the rate of 1 L/hr., reducing progressively to 0.5 L/4 hours depending on the volume status. Once BP and heart rate have stabilized and adequate renal perfusion is assured change over to ½N saline. After the blood sugar has reached 300 mg/ dl, 5% glucose in ½N saline is the most appropriates solution because blood glucose falls before ketones are fully cleared from the circulation. Also, glucose is needed to restore the depleted hepatic glycogen.

• Kc'll Though up to 400 mi of K+ may be lost in urine during ketoacidosis, serum K+ is usually normal due to exchange with intracellular stores. When insulin therapy is instituted, ketosis subsides and K+ is driven intracellularly— dangerous hypokalemia can occur. After 4 hours it is appropriate to add 10–20 meet/hr. Kc to the i.e. fluid. Further rate of infusion is guided by serum K+ measurements and ECG.

• Sodium bicarbonate It is not routinely needed. Acidosis subsides as ketosis is controlled. However, if arterial blood pH is < 7.1, acidosis is not corrected spontaneously or hyperventilation is exhausting, 50 mEq of sod. bicarbonate is added to the i.v. fluid. Bicarbonate infusion is continued slowly till blood pH rises above 7.2.

• Phosphate When serum PO4 is in the low normal range, 5–10 m mol/hr. of sod. /pot. phosphate infusion is advocated. However, routine use of PO4 in all cases is still controversial

• Antibiotics and other supportive measures and treatment of precipitating cause must be instituted simultaneously.

• Hyperosmolar (nonketotic hyperglycemic) coma This usually occurs in elderly type 2 cases. Its cause is obscure but appears to be precipitated by the same factors as ketoacidosis, especially those resulting in dehydration. Uncontrolled glycosuria of DM produces diuresis resulting in dehydration and hemoconcentration over several days → urine output is finally reduced, and glucose accumulates in blood rapidly to > 800 mg/dl, plasma osmolarity is > 350 mom/L → coma, and death can occur if not vigorously treated.

• The general principles of treatment are the same as for ketoacidosis coma, except that faster fluid replacement is to be instituted and alkali is usually not required. These patients are prone to thrombosis (due to hyper viscosity and sluggish circulation), prophylactic heparin therapy is recommended.

• Despite intensive therapy, mortality in hyperosmolar coma remains high. Treatment of precipitating factor and associated illness is vital.

Insulin resistance

When insulin requirement is increased (conventionally > 200 U/day, but physiologically >100 U/day), insulin resistance is said to have developed. However, it may be of different grades.     

1. Acute It develops rapidly and is usually a short-term problem. Causes are—

• Infection, trauma, surgery, emotional stress; corticosteroids and other hyperglycemic hormones may be produced in excess as a reaction to the stress → oppose insulin action. 

• Ketoacidosis—ketone bodies and FFA inhibit glucose uptake by brain and muscle. Also, insulin binding may increase.

• Treatment is to overcome the precipitating cause and to give high doses of regular insulin. The insulin requirement comes back to normal once the condition has been controlled.

• Chronic This is generally seen in patients treated for years with conventional preparations of beef or pork insulins. Antibodies to homologous contaminating proteins are produced which also bind insulin. Very high grades of insulin resistance may be produced in this way. It is more common in type 2 DM.

• Development of such insulin resistance is an indication for switching over to the more purified newer preparations. Some patients may be selectively resistant to beef insulin and respond well to pork or human insulin. After instituting highly pure preparations, insulin requirement gradually declines over weeks and months, and majority of patients stabilize at ~ 60 U/day.

• Pregnancy and oral contraceptives often induce relatively low grade and reversible insulin resistance. Other rare causes are—acromegaly, Cushing’s syndrome, pheochromocytoma, lipoatrophic diabetes mellitus. Hypertension is often accompanied with relative insulin resistance as part of metabolic syndrome.

• Newer insulin delivery devices A number of innovations have been made to improve ease and accuracy of insulin administration as well as to achieve tight glycaemia control. These are:

1. Insulin syringes Prefilled disposable syringes contain specific types or mixtures of regular and modified insulins. 

2. Pen devices Fountain pen like: use insulin cartridges for s.c. injection through a needle. Preset amounts (in 2 U increments) are propelled by pushing a plunger; convenient in carrying and injecting.

3. Inhaled insulin Recently, an inhaled human insulin preparation has been marketed in Europe and the USA. The fine powder is delivered through a nebulizer; absorption is rapid. Peak action occurs at ~2 hours and duration of action is 6–7 hours. It is used to control mealtime glycaemia but is not suitable for round-the-clock basal effect. Less than 10% of inhaled insulin is absorbed. Pulmonary fibrosis and other complications are apprehended on long-term use

4. Insulin pumps Portable infusion devices connected to a subcutaneously placed cannula: provide ‘continuous subcutaneous insulin infusion’ (CSII). Only regular insulin is used. They can be programmed to deliver insulin at a low basal rate (approx. 1 U/hr) and premeal boluses (4– 15 times the basal rate) to control post-prandial glycaemia. Though, theoretically more appealing, no definite advantage of CSII over multidose s.c. injection has been demonstrated. Moreover, cost, strict adherence to diet, exercise, care of the device and cannula, risk of pump failure, site infection, are too demanding on the patient.

5. Implantable pumps Consist of an electromechanical mechanism which regulates insulin delivery from a percutaneously refillable reservoir. Mechanical pumps, fluorocarbon propellant and osmotic pumps are being developed

6. External artificial pancreas This is a microprocessor-controlled device connected through i.v. lines, which measures blood glucose and then infuses appropriate amounts of insulin in a continuous feedback manner. Its size, cost and other problems limit use to only research situations.

7. Other routes of insulin delivery Intraperitoneal, oral (by complexing insulin into liposomes or coating it with impermeable polymer) and rectal routes are being tried. These have the advantage of providing higher concentrations in the portal circulation, which is more physiological

ORAL HYPOGLYCAEMIC DRUGS

• These drugs lower blood glucose levels and are effective orally. The chief drawback of insulin is—it must be given by injection. Orally active drugs have always been searched.

• The early sulfonamides tested in 1940s produced hypoglycemia as side effect. Taking this lead, the first clinically acceptable sulfonylurea tolbutamide was introduced in 1957. Others followed soon after. In the 1970s many so called ‘second generation’ sulfonylureas have been developed which are 20–100 times more potent. Clinically useful biguanide phenformin was developed parallel to sulfonylureas in 1957. Recently 3 newer classes of drugs, viz. α glucosidase inhibitors, meglitinide analogues and thiazolidinediones have been inducted.

SULFONYLUREAS

• All have similar pharmacological profile—sole significant action being lowering of blood glucose level in normal subjects and in type 2 diabetics, but not in type 1 diabetics.

• Mechanism of action Sulfonylureas provoke a brisk release of insulin from pancreas. They act on the so called ‘sulfonylurea receptors’ (SUR1) on the pancreatic β cell membrane—cause depolarization by reducing conductance of ATP sensitive K+ channels. This enhances Ca2+ influx → degranulation. The rate of insulin secretion at any glucose concentration is increased. In type 2 DM the kinetics of insulin release in response to glucose or meals is delayed and subdued. The sulfonylureas primarily augment the 2nd phase insulin secretion with little effect on the 1st phase. That they do not cause hypoglycemia in pancreatectomized animals and in type 1 diabetics (presence of at least 30% functional β cells is essential for their action) confirms their indirect action through pancreas.

• A minor action reducing glucagon secretion, probably by increasing insulin and somatostatin release has been demonstrated. Hepatic degradation of insulin is slowed.

• Extra pancreatic action After chronic administration, the insulinemic action of sulfonylureas declines probably due to down regulation of sulfonylurea receptors on β cells, but improvement in glucose tolerance is maintained. In this phase, they sensitize the target tissues (especially liver) to the action of insulin. This is due to increase in number of insulin receptors and/or a post receptor action—improving translation of receptor activation. It is hypothesized that long term improvement in carbohydrate tolerance leads to a decreased insulin concentration in blood which reverses the down regulation of insulin receptors—apparent increase in their number. A direct extra pancreatic action of sulfonylureas to increase insulin receptors on target cells and to inhibit gluconeogenesis in liver has been suggested but appears to have little clinical relevance.

• Pharmacokinetics All sulfonylureas are well absorbed orally and are 90% or more bound to plasma proteins: have low volumes of distribution (0.2–0.4 L/kg). Some are primarily metabolized—may produce active metabolite; others are mainly excreted unchanged in urine. Accordingly, they should be used cautiously in patients with liver or kidney dysfunction.

Interactions

Drugs that enhance sulfonylurea action (may precipitate hypoglycemia) are

• Displace from protein binding: Phenylbutazone, sulfinpyrazone, salicylates, sulfonamides, PAS.

•  Inhibit metabolism/excretion: Cimetidine, sulfonamides, warfarin, chloramphenicol, acute alcohol intake (also synergizes by causing hypoglycemia). 

• Synergies with or prolong pharmacodynamic action: Salicylates, propranolol (cardio selective β1 blockers less liable), sympatholytic antihypertensives, lithium, theophylline, alcohol (by inhibiting gluconeogenesis). 

Drugs that decrease sulfonylurea action (vitiate diabetes control) are

• Induce metabolism: Phenobarbitone, phenytoin, rifampicin, chronic alcoholism. 

• Opposite action/suppress insulin release: Corticosteroid's, diazoxide, thiazides, furosemide, oral contraceptives.

• Adverse effects Incidence of adverse effects is quite low

• Hypoglycemia It is the commonest problem, may occasionally be severe and rarely fatal. It is more common in elderly, liver and kidney disease patients and when potentiating drugs are added. Chlorpropamide is a frequent culprit due to its long action. Tolbutamide carries lowest risk due to its low potency and short duration of action. Lower incidence is also reported with glipizide, glipalamide, glimepiride.

• Treatment is to give glucose, may be for a few days because hypo glycaemia may recur.

• Nonspecific side effects Nausea, vomiting, flatulence, diarrhoea or constipation, headache, paresthesia's and weight gain.

• Hypersensitivity Rashes, photosensitivity, purpura, transient leukopenia, rarely agranulocytosis.

Chlorpropamide in addition causes cholestatic jaundice, dilutional hyponatremia (sensitizes the kidney to ADH action), intolerance to alcohol in predisposed subjects (flushing and a disulfiram like reaction); other sulfonylureas are less prone to this interaction.

Tolbutamide reduces iodide uptake by thyroid, but hypothyroidism does not occur.

Safety of sulfonylureas during pregnancy is not established—change over to insulin. They are secreted in milk: should not be given to nursing mothers.

BIGUANIDES

Two biguanide antidiabetics, phenformin and metformin were introduced in the 1950s. Because of higher risk of lactic acidosis, phenformin was withdrawn in many countries and has been banned in India since 2003.

They differ markedly from sulfonylureas: cause little or no hypoglycemia in nondiabetic subjects, and even in diabetics episodes of hypoglycemia due to metformin are rare. They do not stimulate pancreatic β cells. Metformin is reported to improve lipid profile as well in type 2 diabetics.

Mechanism of action It is not clearly understood. Biguanides do not cause insulin release, but presence of some insulin is essential for their action. Explanations offered for their hypoglycemics action are.

• Suppress hepatic gluconeogenesis and glucose output from liver: the major action. 

• Enhance insulin-mediated glucose disposal in muscle and fat. Though they do not alter translocation of GLUT4 (the major glucose transporter in skeletal muscle), they enhance GLUT1 transport from intracellular site to plasma membrane. The effect thus differs from that of insulin. 

• Retard intestinal absorption of glucose, other hexoses, amino acids and vit B12. 

• Interfere with mitochondrial respiratory chain—promote peripheral glucose utilization by enhancing anaerobic glycolysis. However, metformin binds less avidly to mitochondrial membrane.

Actions 3 and 4 appear to contribute little to the therapeutic effect.

Pharmacokinetics The important features are given in Table 19.2. Clearance of metformin approximates g.f.r. It accumulates and increases the risk of lactic acidosis in renal failure.

Adverse effects Abdominal pain, anorexia, nausea, metallic taste, mild diarrhoea and tiredness are the frequent side effects. Metformin does not cause hypo glycaemia except in overdose.

Lactic acidosis Small increase in blood lactate occurs with metformin, but lactic acidosis is rare (<1 per 10,000 patient years) because it is poorly concentrated in hepatic cells. Alcohol ingestion can precipitate severe lactic acidosis.

In addition to general restrictions for use of oral hypoglycemics' (see below), biguanides are contraindicated in hypotensive states, cardiovascular, respiratory, hepatic and renal disease and in alcoholics because of increased risk of lactic acidosis.    

MEGLITINIDE / D-PHENYLALANINE ANALOGUES

• These are recently developed quick and short acting insulin releases.

• Repaglinide It is a meglitinide analogue oral hypoglycemic designed to normalize meal-time glucose excursions. Though not a sulfonylurea, it acts in an analogous Mannery binding to sulfonylurea receptor as well as to other distinct receptors → closure of ATP dependent K+ channels → depolarization → insulin release.

• Repaglinide induces rapid onset short-lasting insulin release. It is administered before each major meal to control postprandial hyperglycemia; the dose should be omitted if a meal is missed. Because of short lasting action it may have a lower risk of serious hypoglycemia. Side effects are mild headache, dyspepsia, arthralgia and weight gain.

• Repaglinide is indicated only in type 2 DM as an alternative to sulfonylureas, or to supplement metformin/long-acting insulin. It should be avoided in liver disease.    

• Nate glinide This D-phenylalanine derivative principally stimulates the 1st phase insulin secretion resulting in rapid onset and shorter duration of hypoglycemic action than repaglinide. Ingested 10–20 min before meal, it limits postprandial hyperglycinemia in type 2 diabetics without producing late phase hypo glycaemia. There is little effect on fasting blood glucose level. Episodes of hypo glycaemia are less frequent than with sulfonylureas. Side effects are dizziness, nausea, flu like symptoms and joint pain. It is used in type 2 DM along with other antidiabetics, to control postprandial rise in blood glucose.

THIAZOLIDINEDIONES

• Two thiazolidinediones Rosiglitazone and Pioglitazone are available. This novel class of oral antidiabetic drugs are selective agonists for the nuclear peroxisome proliferator-activated receptor γ (PPARγ) which enhances the transcription of several insulin responsive genes. They tend to reverse insulin resistance by stimulating GLUT4 expression and translocation: entry of glucose into muscle and fat is improved. Hepatic gluconeogenesis is also suppressed. Activation of genes regulating fatty acid metabolism and lipogenesis in adipose tissue contributes to the insulin sensitizing action. Adipocyte turnover and differentiation may also be affected. Thus, fatty tissue is a major site of their action. The magnitude of blood glucose reduction is somewhat less than sulfonylureas and metformin. Improved glycaemia control results in lowering of circulating HbA1C and insulin levels in type 2 DM patients.

• Pioglitazone lowers serum triglyceride level and raises HDL level without much change in LDL level, probably because it acts on PPARα as well. The effect of rosiglitazone on lipid profile is inconsistent.

• Both pioglitazone and rosiglitazone are well tolerated; adverse effects are plasma volume expansion, edema, weight gain, headache, myalgia and mild anemia. Monotherapy with glitziness is not associated with hypoglycemic episodes. Few cases of hepatic dysfunction and some cardiovascular events have been reported; CHF may be precipitated or worsened. Monitoring of liver function is advised. They are contraindicated in liver disease and in CHF. Rosiglitazone has been found to increase the risk of fractures, especially in elderly women.

• Rosiglitazone is metabolized by CYP2C8 while pioglitazone is metabolized by both CYP2C8 and CYP3A4. Failure of oral contraception may occur during pioglitazone therapy. Ketoconazole inhibits metabolism of pioglitazone. Drug interactions are less marked with rosiglitazone.

• The thiazolidinediones are indicated in type 2 DM, but not in type 1 DM. They reduce blood glucose and HbA1c without increasing circulating insulin. Some patients may not respond (nonresponders), especially those with low baseline insulin levels. Glitazones are primarily used to supplement sulfonylureas/metformin and in case of insulin resistance. They may also be used as monotherapy (along with diet and exercise) in mild cases. Reduction in mortality due to myocardial infarction and stroke (macrovascular complications) has been obtained in type 2 DM.

• Several reports associating precipitation of CHF after combined use of glitazones with insulin have appeared; avoid such combinations. They should not be used during pregnancy. The Diabetes Prevention Programme (2005) has shown that glitazones have the potential to prevent type 2 DM in prediabetics.

α GLUCOSIDASE INHIBITORS

• Acarbose It is a complex oligosaccharide which reversibly inhibits α-glucosidases, the final enzymes for the digestion of carbohydrates in the brush border of small intestine mucosa. It slows down and decreases digestion and absorption of polysaccharides and sucrose: postprandial glycaemia is reduced without increasing insulin levels. Regular use tends to lower Hb A1c, body weight and serum triglyceride. These beneficial effects, though modest, have been confirmed in several studies. Further, the stop-NIDDM trial (2002) has shown that long-term acarbose treatment in prediabetics reduces occurrence of type 2 DM as well as hypertension and cardiac disease. In diabetics, it reduces cardiovascular events.

• Acarbose is a mild antihyperglycaemic and not a hypoglycaemic; may be used as an adjuvant to diet (with or without a sulfonylurea) in obese diabetics. Dose 50–100 mg TDS is taken at the beginning of each major meal. It is minimally absorbed, but produces flatulence, abdominal discomfort and loose stool in about 50% patients due to fermentation of unabsorbed carbohydrates. GLUCOBAY 50, 100 mg tabs, ASUCROSE, GLUCAR 50 mg tabs.

• Miglitol is similar to acarbose and is more potent in inhibiting sucrase.

Status of oral hypoglycemics in diabetes mellitus

• After 8 years of prospective study involving large number of patients, the University Group Diabetes Programmed (UGDP) of USA (1970) presented findings that cardiovascular mortality was higher in patients treated with oral hypoglycemics than in those treated with diet and exercise alone or with insulin. A decline in their use followed. Subsequent studies both refuted and supported these conclusions.

• The controversy has now been settled; UK PDS found that both sulfonylureas and metformin did not increase cardiovascular mortality over > 10 years observation period. Related to degree of glycaemia control, both insulin and sulfonylureas reduced microvascular complications in type 2 DM but did not have significant effect on macrovascular complications. Metformin, however, could reduce macrovascular complications as well; it decreased risk of death and other diabetes related endpoints in overweight patients. This may be related to the fact that both sulfonylureas and exogenous insulin improve glycemic control by increasing insulin supply rather than by reducing insulin resistance, while metformin can lower insulin resistance. The thiazolidinediones are another class of drugs which reverse insulin resistance, and have been found to reduce macrovascular complications and mortality in type 2 DM. All oral hypoglycemics do however control symptoms that are due to hyper glycaemia and glycosuria and are much more convenient than insulin.

Oral hypoglycemic's are indicated only in type 2 diabetes, when not controlled by diet and exercise. They are best used in patients with—

• Age above 40 years at onset of disease. 

• Obesity at the time of presentation. 

• Duration of disease < 5 years when starting treatment. 

• Fasting blood sugar < 200 mg/dl. 

• Insulin requirement < 40 U/day. 

• No ketoacidosis or a history of it, or any other complication.

Introduced in the prediabetic ‘impaired glucose tolerance phase’, sulfonylurea + dietary regulation has been shown to postpone manifest type 2 DM. This may be due to the fact that hyperglycemia is a self-perpetuating condition. The Diabetes Prevention Programmed (2002) has established that in middle aged, obese prediabetics metformin prevented progression to type 2 DM, but not in older nonobese prediabetics. Gloxazones appear to have similar potential. Longterm acarbose therapy can also prevent type 2 DM.

Oral hypoglycemics should be used to supplement dietary management and not to replace it. Metformin is preferred in obese type 2 patients: its anorectic action aids weight reduction and it has the potential to lower risk of myocardial infarction and stroke. The gig tolerance of metformin is poorer, and its patient acceptability is less than that of sulfonylureas. Moreover, the sulfonylureas appear to produce greater blood sugar lowering. As such, many patients are treated initially with a sulfonylurea alone. Metformin can be used to supplement sulfonylureas in patients not adequately controlled by the latter.

There is no difference in the clinical efficacy of different sulfonylureas. This however does not signify that choice of drug is irrelevant. Differences between them are mainly in dose, onset and duration of action which governs flexibility of regimens. The second generation drugs are dose to dose more potent, produce fewer side effects and drug interactions, and are commonly used, but no spectacular features have emerged.

Chlorpropamide is not recommended because of long duration of action, greater risk of hypoglycemia, jaundice, alcohol flush, dilutional hyponatremia and other adverse effects. Tolbutamide is less popular due to low potency but may be employed in the elderly to avoid hypoglycemia. Glipalamide and gliclazide are suitable for most patients but have been found to cause hypoglycemia more frequently. Glipizide is preferred when a faster and shorter acting drug is required. Glimepiride is a newer sulfonylurea, claimed to have stronger extra pancreatic action by enhancing GLUT4 translocation to the plasma membrane, thus causing lesser hyperinsulinemia

A low incidence of hypoglycemic episodes has been reported with glimepiride. This may be due to its ability to preserve hypoglycemia induced glucagon release and suppression of insulin release, responses that are attenuated by glipalamide. Glimepiride is suitable for once daily dosing due to gradual release from tissue binding.

Even in properly selected patients, sulfonylureas may fail from the beginning (primary failure 5–28%) or become ineffective after a few months or years of satisfactory control (secondary failure 5–10% per year): may be due to progressive loss of β cells, reduced physical activity, continuing insulin resistance, drug and dietary noncompliance or desensitization of receptors. If one sulfonylurea proves ineffective in a patient, another one (especially a second-generation) may still work. Combined use of a sulfonylurea and a biguanide may be tried if either is not effective alone and the gloxazones are now available as add on/alternative drugs. Patients with marked/only postprandial hyperglycemia may be treated with repaglinide/ Nate glinide. Up to 50% patients of type 2 DM initially treated with oral hypoglycemics ultimately need insulin. Despite their limitations, oral hypoglycemics are suitable therapy for majority of type 2 DM patients. However, when a diabetic on oral hypoglycemic's presents with infection, severe trauma or stress, pregnancy, ketoacidosis or any other complication or has to be operated upon—switch over to insulin

Sulfonylureas and metformin can also be combined with insulin, particularly when a single daily injection of long-acting insulin is used to provide basal control, the oral hypoglycemics' given before meals serve to check postprandial glycaemia.

Guar gum It is a dietary fiber (polysaccharide) from Indian cluster beans (Guar), which forms a viscous gel on contact with water. Administered just before or mixed with food, it slows gastric emptying, intestinal transit and carbohydrate absorption: postprandial glycaemia is suppressed but overall lowering of blood glucose is marginal. It also reduces serum cholesterol by about 10%.

Guargum can be used to supplement diet and to lower sulfonylurea dose, and as a hypocholesterolemic. It is not absorbed but fermented in the colon. Side effects are flatulence, feeling of fullness, loss of appetite, nausea, gastric discomfort and diarrhoea. Start with a low dose (2.5 g/day) and gradually increase to 5 g TDS. DIATAID, CARBOTARD 5 g sachet.

Glucomannan This powdered extract from tubers of Konjar is promoted as a dietary adjunct for diabetes. It swells in the stomach by absorbing water and is claimed to reduce appetite, blood sugar, serum lipids and relieve constipation.

DIETMANN 0.5 g cap, 1 g sachet; 1 g to be taken before meals.

NEWER APPROACHES IN DIABETES

• Exenatide The glucagon-like peptide-1 (GLP-1) is an important incretin that is released from the gut in response to oral glucose. It is difficult to use clinically because of rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4). Exenatide is a synthetic GLP-1 analogue, resistant to DPP-4, but with similar actions, viz. enhancement of postprandial insulin release, suppression of glucagon release and appetite as well as slowing of gastric emptying. It has been marketed in the USA to be used as an additional drug with metformin and/or sulfonylureas in type 2 diabetics who have inadequate response to the oral hypoglycaemics. Exenatide is injected s.c. twice daily 1 hour before meals; acts for 6–10 hours. Nausea is an important side effect.

• Sitagliptin This orally active inhibitor of DPP-4 prevents degradation of endogenous GLP-1 and other incretins, potentiating their action, resulting in limitation of postprandial hyperglycaemia. It is undergoing clinical evaluation as an add-on drug to sufonylurea/ metformin/ thiazolidinediones in type 2 DM.

• Pramlintide This synthetic amylin (a polypeptide produced by pancreatic β cells which reduces glucagon secretion from α cells and delays gastric emptying) analogue attenuates postprandial hyperglycaemia when injected s.c. just before a meal, and exerts a centrally mediated anorectic action. The duration of action is 2–3 hours. It has been marketed as an adjuvant to insulin/ sulfonylureas/metformin for control of meal-time glycaemia in both type-1 and type-2 diabetes.

GLUCAGON

• A hyperglycaemic principle was demonstrated to be present in the pancreatic islets just two years after the discovery of insulin in 1921. It was named ‘glucagon’. Glucagon is a single chain polypeptide containing 29 amino acids, MW 3500. Beef and pork glucagon are identical to human glucagon. It is secreted by the α cells of the islets of Langerhans..

• Regulation of Secretion Like insulin, glucagon is also derived by cleavage of a larger peptide prohormone. Its secretion is regulated by glucose levels, other nutrients, paracrine hormones and nervous system. Glucose has opposite effects on insulin and glucagon release, i.e., high glucose level inhibits glucagon secretion, and it is more sensitive to orally administered glucose: suggesting that the same gastrointestinal incretins which evoke insulin release may be inhibiting glucagon secretion. FFA and ketone bodies also inhibit glucagon release. Amino acids, however, induce both insulin and glucagon secretion. Insulin, amylin and somatostatin, elaborated by the neighboring β and D cells, inhibit glucagon secretion. Sympathetic stimulation consistently and parasympathetic stimulation under certain conditions evokes glucagon release.

• Actions Glucagon is hyperglycemic; most of its actions are opposite to that of insulin. Glucagon causes hyperglycemia primarily by enhancing glycogenolysis and gluconeogenesis in liver; suppression of glucose utilization in muscle and fat contributes modestly. It is considered to be the hormone of fuel mobilization. Its secretion is increased during fasting: this serves to maintain energy supply by mobilizing stored fat and carbohydrate as well as by promoting gluconeogenesis in liver. It plays an essential role in the development of diabetic ketoacidosis. Increased secretion of glucagon has been shown to attend all forms of severe tissue injury.

• Glucagon increases the force and rate of cardiac contraction, and this is not antagonized by β blockers. It has a relaxant action on the gut and inhibits gastric acid production.

• Mechanism of action Glucagon, through its own receptor and coupling Gs protein activates adenylyl cyclase and increases cAMP in liver, fat cells, heart and other tissues; most of its actions are mediated through this cyclic nucleotide.

• Glucagon is inactive orally; that released from pancreas is broken down in liver, kidney, plasma and other tissues. Its t½ is 3–6 min.

Uses

• Hypoglycemia due to insulin or oral hypoglycemics; use of glucagon is secondary to that of glucose; only an expedient measure. It may not work if hepatic glycogen is already depleted: 0.5–1 mg i.e., or a.m. 

• Cardiogenic shock to stimulate the heart in β adrenergic blocker treated patients. However, action is not very marked. 

• Diagnosis of pheochromocytoma 1 mg i.e. causes release of catecholamines from the tumor and markedly raises BP. Phentolamine should be at hand to counter excessive rise in BP.

• GLUCAGON 1 mg inj.3.

• Diazoxide, it inhibits insulin release from β cells and causes hyperglycemia lasting 4–8 hours. Its action on ATP sensitive K+ channels is opposite to that of sulfonylureas. Other actions which may contribute to hyperglycemia are decreased peripheral utilization of glucose and release of catecholamines. It has been used to prevent hypoglycemia in insulinomas.

• Thiazide diuretics and phenytoin These are also mild hyperglycemic.

• Somatostatin It causes hyperglycemia primarily by inhibiting insulin release.

• Streptococci It is obtained from Streptomyces chromogens. Causes selective damage to insulin secreting β cells. It has been used to produce experimental diabetes in animals and to treat insulin secreting tumors of pancreas.