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Health Administrator Vol: XXII Number 1& 2 - 2009 : 143-148

32 - CURRENT MODALITIES IN THE TREATMENT OF NON-INSULIN DEPENDENT DIABETES MELLITUS


ABSTRACT In the therapy of Type -2 / non-insulin dependent diabetes mellitus, current agents are lacking in the ideal euglycaemic control. Putative agents attack the heterogeneous pathogenicity and have varied sites of action. Insulin action enhancers, secretogogues, metabolic modulators and drugs with direct action through the gastro intestinal tract, show promise in the pharmaco therapy of diabetes. (The Ind. Pract. 2002;55(12);790-796) INTRODUCTION The prevalence of diabetes is on the rise globally. The long asymptomatic phase, general misconception that it is a mild disease and apathy towards its treatment, leads to this grim scenario, where 20% of patients, present with micro or macro vascular complications. NEED FOR NEWER DRUGS The limitations of current anti-diabetic therapies are: (1) Current agents offer, a range of actions to reduce hyperglycaemia. Oral agents are used first or in combination with insulin when on-going beta cell failure and hyperglycaemia becomes severe. (2) Individual agents act only on a part of the process underlying the derangement and that too, only to a limited extent. They do not prevent gradual beta cell loss and their usefulness depends upon a critical mass of functioning beta cells. D. (4) They do not reinstate normal insulin sensitivity or normal beta cell function. 143 Others: Erythromycin A. ATP sensitive Potassium Channel Inhibitors (i) (ii) Sulphonylureas-Tolbutamide Benzoic Acid. Derivatives - Meglitimide

Current Modalities In Therapy of NIDDM 1. Drugs acting on Gastro Intestinal Tract

A.

Stomach and Intestine Acarbose, Vigabose Miglitol Amylin Analogues - Pranlintimide Plant Fibre Supplements - Guar, wheat bran Dietary supplemnts Vitamin E, Vitamin C,

B.

PANCREAS:

Gene Therapy II Insulin Secretagogues

B. Glucagon - like peptide inhibitors Exendin - 4. C. Benzamido derivatives - Repaglimide,

(3)

Nateglimide

Glyceraldehydes Phosphate Succinated Esters

Insulin Analogues ON THE GASTRO

III Insulin Action Enhancers

I.DRUGS ACTING INTESTINAL TRACT a)

Drugs Acting On The Stomach and Intestine. Drugs Acting On Pancreas

A. B. 1. 2. i) ii)

Insulin Mimetics Vanadyl Sulphate Manganese and Selenium Salts Human Growth Hormone Fragments Insulin Sensitisers Biguanides - Metformin Thiazolidinediones Rosiglitazone Troglitazone

b)

A. Stomach And Intestine

These agents have a unique role in decreasing the digestion and absorption of Carbohydrates and fats. This allows for better glycaemic control. i) Acarbose: (Vigabose) It is an
oligosaccharide obtained from Actinophanus utachensis. This group of drugs competitively inhibits the enzyme - a glycosidase, at the level of small intestinal brush border cells. This enzyme is responsible for breakdown of complex polysaccharides and sucrose to glucose. This results in decrease in postprandial hyperglycaemia and consequently the need for insulin. Adverse Effects: Flatulence, cramps, diarrhea Dosing Schedules: 200 mg, 50 mg, three times a day along with major meals. ii) Miglitol: structure is chemically very similar to that of glucose. The absorption from gastro intestinal tract is complete. It has a short

IV Metabolic Modulators

A. B. C.

Glucose Metabolism Lipid Metabolism Clomoxir Etomocxir BRL5235 Antiobesity Agents Fenfluramine Phentermine Sibutramine

duration of action and lesser side effects. When compared with acarbose. It effectively decreases postprandial hyperglycaemia. Doses employed are 50 to 100 mg. iii) Amylin Analogues: mainly act by slowing the gastric emptying and delays the absorption of nutrients. The adverse effects mainly comprise nausea and complication of delayed gastric emptying. Doses employed

V. Insulin

Aerosolized Insulin Tetramers

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are 30 mg 3 times a day. Intravenous or subcutaneous infusions E.g. Pramlintide. iv) Plant Fibre Supplement: These include non-starch polysaccharides, obtained from lignin. They form a diffusional barrier by entrapping carbohydrate within their matrix. They also decrease the rate of carbohydrate digestion by decreasing the interaction between carbohydrate and the brush-border enzymes. Formulations (a) Soluble (i) Guar - They prolong gastric emptying and extend intestinal transit time. b) I nsoluble: (i) Wheat bran - They reduce the intestinal transit time. Soluble fibre supplements should be taken with ample water and preferable mixed or consumed with or at the same time as a meal. The adverse effects though mild are annoying like unpalatability, abdominal distension and flatulence.

of beta cells would affect the aetiopathogenesis and prevent the development of non-insulin dependent diabetes mellitus. Such potential agents are, only, on the worktable of scientists and have not yet got to the stage of clinical trials. Putative agents can also affect by increasing the biosynthesis and processing of proinsulin, and selectively enhancing the release of insulin in response to glucose. Incorporation of surrogate beta cells done with gene therapy is a welcome advantage. Gene Therapy Gene Therapy offers the means of insulin supplements without daily interventions by the patient. Somatic cells and not, the beta cell is taken from the diabetic donor. Genetic engineering of the cell to produce insulin is undertaken and returned to the donor. This is achieved by introducing and activating new, copies of genes, encoding prepro insulin and the enzymes required for processing the insulin. Advantages (1) Selecting a cell such as, a fibroblast, for somatic gene therapy offers the advantage of minimal surgical intervention. Immuno suppression is not required since patients own cells are implanted. The performance of the engineered cells can be assessed in-vitro, before implantation. Extra cells may be cryopressed for later use. (4) Implantation can be encapsulated, to guard against uncontrolled growth and to facilitate retrieval, at a later date.

V.

Dietary

Supplements:

Magnesium

supplements can improve glycaemic control and insulin sensitivity especially in hypomagnesaemic patients. So also, trivalent chromium compounds through an unexplained mechanism achieves euglycaemic control. Molybdenum salts have been speculated to have a unique role in insulin action. Antioxidant vitamin supplements e.g. Vitamin C, Vitamin E and beta-carotene has shown considerable evidence in animal models. B Pancreatic Beta Cell The insulin hormone secreting cells are Beta cells and they are definitely the targets for manipulation so as to impart increased circulating insulin levels. Decreased apoptosis and other mechanisms of loss of beta cells, as wells as, enhancing the growth, differentiation and maturation

(2)

(3)

Disadvantages Diabetes Mellitus is not a single gene disease. Chromosomes 2, 6,11,15 are encoded and more 145

than one gene is involved. Following upon this conclusion, it is not certain how many genes can be manipulated, at a time? If this can be achieved then, NIDDM can be conquered in terms of gene therapy. II INSULIN SECRETAGOGUES They act by increasing circulating insulin levels, mainly by three mechanisms. 1. 2. 3. Induce insulin secretion Potentiate nutrient induced insulin release antagonize inhibitors of insulin secretion

Advantages 1. It prevents prolongation of hyperinsulinaemia

and reduces the risk of inter prandial hypoglycaemia. 2. They reinstate a first phase surge of insulin release into the portal preventing effective suppression of hepatic glucose output. E.g.: Repaglinide, Nateglimide. D) a) b) c) i) ii) d) Other Insulin Releasers Inhibitors of Phosphodiesterase -L 686398 Antagonists of Alpha adrenoceptors: Metabolic stimulants; Glyceraldehyde phosphate, Succinated esters. Unestablished mechanisms of action; Erythromycin III INSULIN ACTION ENHANCERS A. B. A. Insulinomimetics Insulin Sensitisers Insulinomimetics Many substances can act independent of insulin to lower blood glucose level and mimic some effects of insulin on cellular membrane. I Vanadium Compounds: e.g. Vanady 1 and Vanadate salts. They lower blood glucose levels to near normal levels in obese and non-obese animal models. Advantages 1) They stimulate glucose uptake by oxidation and glycogenesis by skeletal muscle; and oxidation and lipogenesis in adipose tissue.

Drugs in this group are A) Atp - Sensitive Potassium channel

Inhibitors They close the ATP sensitive Potassium Channels causing membrane depolarization, which results in insulin release. They require sufficient glucose to support the metabolic needs of the beta cells. E.g. 1. Sulphonylureas e.g: Tolbutamide 1. Benolic acid derivatives. HB699 Meglitimide. B) Glucagon - Like Peptide Inhibitors These drugs potentiate nutrient induced insulin release via receptors on beta cells which active cAMP. They increase insulin biosynthesis via cAMP - phosphokinase pathway. They appear to slow gastric emptying time and induce satiety. Being a rapidly degraded peptide, its therapeutic application is limited by the need for infusion or repeated injections. C) Benzamido Derivatives These drugs when taken with a meal, restricts the stimulation of insulin release to the period of meal digestion.

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2)

They facilitate insulin release by increasing phosphodiesterase turnover and intracellular Calcium metabolism in the intact beta cell. T h e y a ct a s a p p et i t e s u p pr e s s a n t s a n d decrease the intestinal absorption of Glucose.

I.

Biguanides

E.g.; Metformin, phenformin These drugs inhibit gluconeogenesis; hepatic glucose output; improve insulin sensitivity. II Thiazolidinediones E.g. Troglitazone, Rosiglitazone, Meglitazone, Proglitazone, isaglitazone. These drugs bind to the Prioxosome Proliferator Activated Receptor - PPARa and on the Retinoid X Receptor-RXR, which is strongly expressed in the adipose tissue. This binding increases the transcription of certain insulin sensitive genes PPAR gamma is an orphan nuclear receptor. When these receptors are stimulated by Thiazolidenediones - (TZDD),they promote expression of genes encoding -lipoprotein lipase; Fatty acid transcription protein; adipocyte fatty acid binding protein; fatty acyl co-A synthase; and insulin sensitive glucose transporter - GluT-4. these agents increase the action of insulin in these tissues by increasing fatty acid uptake, lipogenesis and glucose uptake, improve glucose fatty acid cycle and reduces gluconeogenesis. But the drawbacks of these agents are: Hepatotoxicity, haemodilution and increase in plasma cholesterol. IV METABOLIC MODULATORS A) B) C) A) Glucose Metabolism Lipid Metabolism Antiobesity Drugs Glucose Metabolism Modulators

3)

Disadvantages 1. They are poorly absorbed from the alimentary tract. 2. They have a narrow therapeutic margin.

Hence less toxic, more potent and readily absorbable vanadium compounds are under investigation. II Manganese and Selenium Salts: Trace elements like manganese and selenium salts are under investigation for the same purpose. III Human Growth Hormone Fragments These fragments exert an insulin - like and an insulin antagonist - like action. They cause increased insulin mediated glucose uptake, oxidation and glycogenesis in muscle and fat (but has no action in the absence of insulin.) Analogues with the "minimum structure" required for maintaining insulin - like effect is under consideration. B. Insulin Sensitizers

They are potentiators of insulin action. These agents have an important role in assuaging the universal phenomenon pf "insulin resistance", that occurs in most of the long-standing cases of NIDDM. i) ii) Bibuanides Thiazolindenediones.

Agents that act directly to stimulate glucose uptake and in theory, overcome the under-utilization of glucose in muscle has been developed and is in the stage of clinical trials.

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B) Manipulators of Lipid Metabolism Interventions which limit the availability of fatty acids or inhibits their oxidation, offers increasing utilization of glucose and inhibits gluconeogenesis. Antilipocytic Agents; i) Fibric acid and Nicotinic acid derivatives: These agents reduce free fatty acid and nicotinic acid, especially, induces lipolysis. ii) Adenosine: Adenosine reduces lipolysis in adipocytes by inhibiting cAMP formation and improving insulin sensitivity. iii) Inhibitors of fatty acid oxidation: e.g.: Clonoxir, Etonoxir. They inhibit the enzyme carnitine palituyl transferase, which is the rate limiting enzyme for transfer of long chain fatty acyl co A, in the mitochondria. iv) B3 Adrenoceptor Agonist: E.g. - BRI 5235. They increase energy expenditure by stimulating thermogenesis on brown adipose tissue and increases lipolysis in white adipose tissue and improves glucose tolerance.

V INSULIN Insulin only, can be the ideal therapy, in lieu, of oral antidiabetic agents for effective treatment of NIDDM. Aerosolized insulin tetramers and insulin analogues with rearrangements on the amino acid sequences are the preferred options. Hence, the day-long acting basal insulin supplementation makes way for supplementations that are synchronous with the natural surges of insulin. CONCLUSION There is now an increased awareness, for the optimal glycaemic control and pitfalls of available therapeutic options in NIDDM. Hence the renewed search for new modalities of therapy. Despite the exciting treatment targets outlined, herein, no single agent is capable of halting the inseparable metabolic decompensation of NIDDM. This, elusive agent, is hoped for by the new millennium scientist, that would hit hard on the basic pathogenesis of NIDDM, with fewer adverse effects. Thus such, panacea, will rescue the diabetic patient from the doldrums of morbidity.

C.

Antiobesity Agents

These agents have proven themselves to have clinically useful blood glucose and lipid lowering levels, e.g. Fenfluramine, Sibutramin, Phentermine, Dexfluramine.

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