Revista diabetes 2 2009 by felipe espino

Editorial La revista Diabetes Internacional publica su segundo número del volumen 1 de 2009. Se aceptaron dos artículos de revisión por reputados investigadores. El profesor Zafar Israili hizo una extensa revisión del tema de las drogas moduladoras del sistema incretina que ha generado un grupo de drogas antidiabéticas, hasta el momento tenemos en el mercado venezolano la sitagliptina (januvia) y la vidagliptina (galvus), ambas de dos casas comerciales internacionales. El profesor Valmore Bermúdez y su grupo de investigación en diabetes mellitus de Maracaibo han revisado la alimentación en la genealogía de la diabetes. Aportan datos que el tipo de alimentación del ser humano que usualmente se basa en ingesta de altos carbohidratos y grasas saturadas puede inducir la diabetes en presencia de aspectos hereditarios y situaciones de stress.

Editores en Jefe Dr. Manuel Velasco Dr. Valmore Bermúdez Dr. Luis Fernando Chacín

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Editores

Editores en Jefe Velasco Manuel (Venezuela) Bermúdez Valmore (Venezuela) Chacín Luis Fernando (Venezuela) Editores Ejecutivos Gaslonde Luis (Venezuela) Contreras Freddy (Venezuela)

Comité Editorial Arciniegas Enrique (Venezuela) Bolli Peter (Canadá) Bustos Elizabeth (Venezuela) Camejo Manuel (Venezuela) Cordero Marilin (Venezuela) Cubeddu Luigi (USA) Crippa Giuseppe (Italia) De Santis Juan (Venezuela) Escobar Edgardo (Chile) Feldstein Carlos (Argentina) Hernández Rafael (Venezuela) Israili Zafar (Estados Unidos) Lares Mary (Venezuela) Levenson Jaime (Francia) López Jaramillo Patricio (Colombia) López Mora José (Venezuela)

Lucani Miguel (Venezuela) Manfredi Roberto (Italia) Mathison Yaira (Venezuela) Marante Daniel (Venezuela) Morales Eduardo (Venezuela) Muci Rafael (Venezuela) Obregón Oswaldo (Venezuela) Palacios Anselmo (Venezuela) Parra José (México) Ruiz Miguel (Venezuela) Salaverria Nancy (Venezuela) Sanabria Tomas (Venezuela) Silva Honorio (USA) Stulin Irene (Venezuela) Urbina Douglas (Venezuela) Zanchetti Alberto (Italia)

Sumario

Volumen I, Nº 2, 2009 Treatment of type 2 diabetes mellitus by drugs modulating the incretin system Zafar H. Israili

La alimentación en la genealogía de la diabetes Food genealogy in diabetes

Maryluz Núñez Pacheco, Ángel Alberto Oroño García, Rafael Lopez Sanz, Abdón Toledo, Maricarmen Chacín, Edgardo Mengual, Roberto Áñez, Valmore Bermúdez Pirela y Manuel Velasco

COPYRIGHT Derechos reservados. Queda prohibida la reproducción total o parcial de todo el material contenido en la revista sin el consentimiento por escrito de los editores. Volumen 1, Nº 2, 2009 Depósito Legal: pp200902DC3118 ISSN: 1856-965X www.diabetesinternacional.com Dirección: Escuela de Medicina José María Vargas Cátedra de Farmacología, piso 3. Esq. Pirineos. San José. Caracas-Venezuela. Telfs. 0212-5619871/0212-565.1079/ Cel. 0414-1361811 manuel.veloscom@gmail.com / veloscom@cantv.net E-mail:diabetesinternacional@gmail.com Comercialización y Producción: Felipe Alberto Espino Telefono: 0212-881.1907/ 0416-811.6195 / 0412-363.45.40 E-mail: felipeespino7@gmail.com

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Diseño de portada y diagramación: Mayra Gabriela Espino Telefono: 0412-922.25.68

E-mail: mayraespino@gmail.com

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Treatment of type 2 diabetes mellitus by drugs modulating the incretin system

Zafar H. Israili Department of Medicine, Emory University School of Medicine, Atlanta, Georgia USA Address for correspondence: Dr. Zafar H. Israili, Department of Medicine, Emory University School of Medicine, 69 Jesse Hill Jr. Drive, Atlanta, Georgia 30303, USA. Tel: 678-480-5860 e-mail: zisrail@emory.edu Recibido: 02/02/2009

Aceptado: 20/02/2009

Abstract (incretin mimetics) have been developed. Since, the incretin mimetics have to be injected, orally active inhibitors of DPP-4, the incretin enhancers, have also been introduced for the treatment of T2DM. The GLP-1 receptor agonists and DPP-4 inhibitors are useful in the management of T2DM because they provide effective reductions in levels of fasting plasma glucose (FPG) and postprandial glucose (PPG), partly through their actions on pathogenic causes of T2DM that are not addressed by other glucoselowering agents. In addition, the GLP-1 receptor agonists promote weight loss, whereas the DPP-4 inhibitors are mostly weight neutral, and there is a low risk of symptomatic hypoglycemia with both type of agents. The GLP1 receptor agonists and DPP-4 inhibitors are effective as monotherapy in drug-naive patients as well as in those in whom other treatments (for example with metformin, sulfonylureas, thiazolinediones, etc.) have been inadequate to achieve glycemic control. When combined with other glucose-lowering agents, the GLP-1 receptor agonists and DPP-4 inhibitors further lower FPG and PPG levels, and hemoglobin A1c. Consequently, these agents can be used for all stages of T2DM. However, the durability and long-term safety of these drugs remains to be determined. This review focuses on the therapeutic potential of the incretin mimetics and incretin enhancers in treating T2DM. In addition, the review also presents some information on the mechanism of action(s), efficacy, pharmacokinetics, pleiotropic effects, drug interactions and adverse effects of the main drugs which modulate levels and activity of endogenous incretins.

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Diabetes, specifically type 2 diabetes mellitus (T2DM), one of the most common non-communicable diseases, poses a major health problem throughout the world. T2DM is characterized by insulin resistance, impaired glucose-induced insulin secretion and inappropriately regulated glucagon secretion which in combination eventually result in hyperglycemia and in the longer term microvascular and macrovascular complications of diabetes. Traditional treatment modalities, even multidrug approaches, for T2DM are often inadequate in getting patients to achieve glycemic goals as the disease progresses due to a steady, relentless decline in pancreatic β-cell /number/function. Furthermore, current treatment modalities are often limited by inconvenient dosing regimens, safety and tolerability issues, the latter including hypoglycemia, body weight gain, edema and gastrointestinal side effects. A novel category of antihyperglycemic therapy based on modulation of the endogenous incretin system has recently evolved. The incretins, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are gut-derived peptides secreted in response to meals, specifically the presence and absorption of nutrients in the intestinal lumen. The incretins potentiate meal-induced insulin secretion and trophic effects on the β-cell; the GLP-1 also inhibits glucagon secretion, and suppresses food intake and appetite. The activity/level of the incretins is diminished in T2DM. Both GLP-1 and GIP are rapidly degraded by the endogenous dipeptidyl-peptidase-4 (DPP-4). Hence, stable long-acting GLP-1 analogs/GLP-1 receptor agonists

Introducción Diabetes, specifically type 2 diabetes mellitus (T2DM), one of the most common non-communicable diseases, is emerging as an epidemic of the 21th century and a major health problem throughout the globe1,2. Complications from diabetes, such as cardiovascular (CV) disease, peripheral vascular disease, stroke, diabetic neuropathy, amputations, renal failure and blindness result in increasing disability, reduced life expectancy and enormous health costs for virtually every society4. T2DM is a polygenic disease characterized by multiple defects in pancreatic insulin secretion and insulin action in muscle, adipose, and liver3. About 80-85% of T2DM patients have insulin resistance, and impaired β-cell function occurs in 50% of newly diagnosed T2DM5,6, and after that there is a linear decline in β-cell number/function with time, despite therapy with sulfonylurea, metformin or insulin7,8, as a result of glucotoxicity, lipotoxicity, proinflammatory cytokines, leptin, and islet cell amyloid leading to accelerated apoptosis and loss of β-cell function/mass. The treatment goals for T2DM patients are related to effective control of blood glucose, as well as management of coexisting pathologies, such as hypertension, dyslipidemia, and excess body weight, and ultimately, to avert the serious complications associated with sustained tissue exposure to hyperglycemia. Although, intensive glycemic control reduces the appearance and progression of microvascular and neuropathic complications (retinopathy, nephropathy and neuropathy)9-12, long-term intensive therapy to achieve target HbA1c in T2DM patients has been associated with increased mortality without significant beneficial effect on major CV events13. In addition, tighter glycemic control (using intensive therapy) burdens the patients with complex treatment regimens, increased risk of hypoglycemia, possible weight gain, and relatively high costs, while offering uncertain benefits in return14-16. Hence, ideal treatment in T2DM should be to control hyperglycemia and its adverse consequences without increasing CV or other risks such as hypoglycemia, by healthy lifestyle, preventive care, and individualizing and optimizing medications (combinations, if necessary) and their doses, for initiation and intensification of therapy to achieve a target hemoglobin A1c (HbA1c), depending on patients’ circumstances.

Prevention and control of diabetes with diet, weight control and physical activity has been difficult. Treatment of T2DM has centered on a) increasing insulin levels, either by direct insulin administration or oral agents that promote insulin secretion (insulin secretagogues, such as oral sulfonylureas), b) improving insulin sensitivity to insulin in tissues, such as by metformin or thiazolidinediones (TZDs), or c) reducing the rate of carbohydrate absorption from the gastrointestinal tract by the use of α-glucosidase inhibitors and/or agents that decrease gastric motility. Despite significant improvement achieved over the last

decade in the management of T2DM with the use of drugs such as metformin, sulphonylureas, α-glycosidase inhibitors, TZDs and insulin preparations, often in high doses and in combinations, a large proportion of patients are unable to reach recommended therapeutic targets (>60% with HbA1c > 7%)6,7,9,17. Furthermore, current treatments do not address the issue of progressive β-cell dysfunction/ failure/loss, such that the development and continued progression of diabetes is a consequence of the failure of the β-cell to overcome insulin resistance. In addition, current therapies, with the exception of insulin, have limited glucose-lowering capacity, and become less effective over time as a result of progressive loss of β-cell function/ number.17 Also, there are major adverse effects associated with the use of current medications, especially weight gain2,18, which may undermine the benefits of glycemic control. Therefore, strategies that aim to prevent hyperglycemia must also aim to stabilize the progressive decline of β-cells. In this regard, intensive efforts have been made and are still continuing to develop newer classes of drugs to control hyperglycemia in T2DM patients without insulin and preserve β-cell number/function. Recent breakthroughs in the understanding of incretin-based therapies have provided additional options for the treatment of T2DM, and one of the main strategy has been to modulate the levels of incretins (see below), the endogenous substances involved in glucose control to treat T2DM. This review describes the therapeutic potential in treating T2DM (used as monotherapy or in combination with other antidiabetic drugs), mechanism of action(s), efficacy, pharmacokinetics, pleiotropic effects, drug interactions and adverse effects of the main drugs which modulate levels and activity of endogenous incretins. The incretins In 1902, Bayliss and Starling proposed that intestinal mucosa contains a hormone that stimulates the exocrine secretion of the pancreas (“secretin”). In 1932, La Barre proposed the name incretin for a hormone extracted from the upper gut mucosa, which caused hypoglycemia and proposed possible therapy for diabetes. In 1970, gastric inhibitory peptide (GIP) was isolated from intestinal mucosa and sequenced by Brown and co-workers. The original name gastric inhibitory peptide was dropped and GIP was renamed glucose-dependent insulinotropic peptide in 1973 after Brown and colleagues, showed that GIP (Table 1) stimulates insulin secretion19. Of the several glucagon-like peptides-1 (GLP-1) detected in the intestinal secretions, the GLP-1 (7-36) amide, was found to have the insulinotropic effect in humans21,22. It was determined that the incretin effect is mainly due to GLP-1(736) amide and GIP (Figure 1). GLP-1 (7-36) is a 30 amino acid peptide produced (from proglucagon) and released from the neuroendocrine L-cells of the lower small intestine (ileum) and the colon, in response to dietary fat and carbohydrates21-24, while GIP is a 42-aminoacid peptide secreted from the K-cells of mainly the duodenum and

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jejunum20,23. Both endogenous incretins have a very short half-life (t), of the order of minutes, as a result of degradation by the serum enzyme dipeptidyl-peptidase-IV (DPP-4, CD-26, EC 3.4.14.5)25-28. GLP-1 (7-36) is rapidly degraded (Table 1) to GLP-1 (9-36) with a plasma t½of 1–2 minutes, while GIP is also quickly degraded with a t½= 4.3 min to GIP (3-42)20,23-27. Earlier, it was thought that the degradation products of GIP and GLP-1 were inactive, however, it has been shown that some of the extra-pancreatic effects of GLP-1 (lowering of post-prandial glycemia by decrease in hepatic glucose production and vasodilatory effect) are mediated via the metabolite GLP-1 (9-36)28,29, and improvement in insulin sensitivity by GIP (3-42)29. Figure 1

tors, is the product of a gene mapped to the short arm of human chromosome 6 (6p21.1) and binds specifically GLP-1; it has a much lower affinity for related peptides such as GIP and glucagon21,26,30,31. GIP has a GIP-specific G-protein-coupled receptor with no cross-reactivity with the GLP-1 receptor. 22,30,31 Intravenous administration of GLP-1 activates the GLP-1 receptor, which results (Table 2) in a) increased cAMP production and activation of ATPsensitive K channel mediated by β-arrestin-132,33, leading to increased synthesis and release of insulin; b) glucosedependent enhancement of insulin release by improving β-cell responsiveness to glucose via increased expression of glucose transporter-2 (GLUT 2) and glucokinase genes; insulin release is high at high glucose level and decreases as the glucose level drops, c) increase in tissue sensitivity to insulin, d) glucose-dependent secretion of amylin from the pancreas, e) delay in gastric emptying, mediated by vagal afferents34, f) suppression of appetite (by a central mechanism, possibly partially mediated by increased serotonin release in the hypothalamus35, and producing a feeling of fullness36, and satiety37, leading to decreased body weight, g) improvement in glycemic control, and h) decrease in glucagon secretion (from α-cells), possibly mediated by increased somatostatin secretion, resulting in reduced hepatic glucose production (Table 2)21-23,26,38. Interaction of GIP with its receptor also increases glucose-dependent pancreatic insulin secretion, but it has no effect on hepatic glucose output, gastric motility, satiety or body weight (Table 2), however, it does induce lipogenesis and glucagon secretion, and suppress

Table 1. Amino acid sequence of incretins and analogs 

GLP-1

(7-36; human)

HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-amide

GLP-1

(9-36; human)

EGTFTSDVSSYLEGQAAKEFIAWLVKGR-amide (metabolite of GLP-1) 

GIP (1-42; human)

YAEGT-FISDY-SIAMD-KIHQQ-DFVNW-LAQKG-KKNDW-KHNHI-TQ

GIP (3-42; human)

EGT-FISDY-SIAMD-KIHQQ-DFVNW-LAQKG-KKNDW-KHNHI-TQ (metabolite of GIP)



Exendin-4 (synthetic) (Exenatide)

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-amide

Exendin (9-39)

DLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-amide (major circulating metabolite of exendin-4)



Liraglutide (1-31) HAEGTFTSDVSSYLEGQAAKEFIAWLVRGR | C-16-fatty acid-albumin -----------------A = Ala; D = Asp; E = Glu; F = Phe; G = Gly; H = His; I = Ile; K = Lys; L = Leu; M = Met; N = Asn; P = Pro; R = Arg; Q = Gln; S = Ser; T = Thr; V = Val; W = Trp; Y = Tyr The position of action of the enzyme DPP-4 is indicated by (above) to give the respective metabolites; other metabolites are also formed by the action of various enzymes.

Incretin receptors Both the incretins have specific receptors. The GLP-1 receptor, a member of the seven-transmembrane domain glucagon receptor family of G-protein-coupled recep-

gastric acid secretion23,26,28. In addition to improving insulin sensitivity, the incretins also promote proliferation/ neogenesis of β-cells and prevent loss of β-cells by apoptosis, stimulate proinsulin gene transcription and transla-

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tion39,40,23,26,28. Additionally, there are several mechanisms of regulating hepatic and muscle glucose flux via GLP-1 receptor, independent of insulin effect41,42. Receptors for both GLP-1 are found in the pancreatic islet β-cells, as well as in the stomach, adipose tissue, skeletal muscle, bone, heart, kidney, stomach, lung and brain20,21,23,27 and GIP receptors are mainly expressed in β-cells23,27. Table 2. Comparative actions of GLP-1 and GIP Increase glucose-dependent insulin secretion (from pancreatic β-cells)

Yes

Yes*

Enhance insulin sensitivity

Yes

Suppress glucagon secretion (from pancreatic α-cells)

Yes

No*

Stimulate insulin biosynthesis

Yes

Decrease apoptosis of β-cells

Yes

Lower blood glucose

Yes

Inhibit gastric emptying (decrease gastric motility)

Yes

Inhibit gastric acid secretion

Yes

Inhibit hepatic insulin extraction

Yes

Inhibit post-prandial glucose excursion

Yes

Extrapancreatic glucose lowering

Yes

Enhance satiety (suppress appetite)

Yes

No*

Yes

No*

Decrease body weight Enhance β-cell survival Increase β-cell neogenesis Stimulate β-cell expansion (mass) ------------------------------------------------------------ * = the effect is not consistent

Incretins in normoglycemic individuals and in patients with type 2 diabetes mellitus In healthy normoglycemic individuals, plasma glucose levels are maintained within a narrow range by pancreatic insulin and glucagon (having opposite effects on glucose), and by glucoregulatory hormones, amylin and the incretins (GLP-1 and GIP)22,23. Ingestion of nutrients results in the release of the incretins, which stimulate the release of insulin from the pancreatic β-cells20,21. Incretin action is required for glucose homeostasis (24-hr blood glucose control) as well as control of postprandial glucose; about 50-70% of stimulation of insulin secretion after a meal is due to incretin effect39,40.

effect is either greatly impaired as a result of decrease in postprandial GLP-1 secretion (about 15%) and a marked reduction in insulinotropic response of β-cells to GIP25,43-46; hyperglycemia decreases the levels of GIP and GLP-147. The reduced incretin effect is believed to contribute to impaired regulation of insulin and glucagon secretion in T2DM. This impaired action of incretins in T2DM patients may be, at least partly, restored by improved glycemic control, as shown in studies involving intensive GLP-1 GIP diabetic therapy39,48.

In T2DM, the amount of insulin released from the β-cells in response to a meal is insufficient and/or the target tissues (fat, liver and muscle) develop insulin resistance (decreased insulin sensitivity). In addition, the incretin

Treatment of type 2 diabetes mellitus based upon modulation of incretins An option for the treatment of T2DM involves modulation of levels of endogenous incretins, mainly GLP-1, which control the release of insulin and glucagon from the pancreas in response to meals. Since, the levels of GLP-1 are decreased in T2DM43-46 and both GLP1 and GIP have a very short t, of the order of minutes, as a result of degradation by DPP-420,23,27, enhancement of incretin action has been achieved by the development of novel metabolically stable activators of the GLP-1 receptor (incretin-mimetics)47-70, as well as, by inhibitors of DPP-4 (incretin enhancers)39,49,52,56-60,62-65,67,69-83,84.

GLP-1 receptor agonists -- Incretinmimetics Because of very short t, native GLP-1 is Yes Yes not useful as a therapeutic agent unless administered by continuous subcutaneYes Yes ous infusion24,61. Hence, several synthetYes Yes ic incretin-mimetics with longer t have recently been introduced, such as the exendins, which act by stimulating the GLP-1 receptors, and thus, stimulating glucose-dependent insulin secretion and inhibiting glucagon release after meals. Exendin-4, a 39 amino acid peptide found in the saliva (venom) and isolated from the salivary gland of the lizard Heloderma suspectum (Gila monster)85, is a naturally occurring analog of GLP-1 (53% homology to GLP-1) (Table 4), that binds and activates the GLP-1 receptor with the same potency as GLP-186-87. A synthetic version of exendin 4 (exenatide, 39-aminoacid peptide, Byettta®) is an insulin secretagogue with glucoregulatory effect, which has been approved in the USA (2005) as add-on therapy in T2DM patients with metformin, TZDs, sulfonylureas, and/or insulin to improve glucose control88-90. Though the effects of exendin-4 (exenatide) treatment on glucose control are likely due to several actions that are similar to those of GLP-1, the activity of exendin-4 is much greater than that of GLP-1 in controlling hyperglycemia, which may be due to its resistance

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to degradation by DPP- 491. In human plasma it has a t½of 9.6 hr92, but in the circulation the t is 2.4 hr93. In response to a meal, exenatide a) causes initial rapid release of insulin (from β-cells), b) suppresses pancreatic glucagon release, c) delays gastric emptying and thus decreases appearance of glucose after a meal, and d) reduces appetite - all of which function to lower blood glucose55,90,91. The results of the clinical studies with exenatide have been reviewed56-58,62,65,70,94; some data are presented in Table 4, which demonstrate that exenatide improves glycemic control (reduces HbA1c by 0.8%1.4%) and decreases body weight by ~2-4 kg in T2DM patients88,94-110, who fail to achieve glycemic control with metformin and/or a sulfonylurea. Monotherapy with exenatide (5-10 g/dose) for 24 weeks in T2DM patients, in

addition to decreasing HbA1c (0.7-0.9%), resulted in a significant weight loss (2.8-3.1 kg)95. Most patients using exenatide slowly lose weight, and generally the greatest weight loss is achieved by people who are the most overweight at the beginning of exenatide therapy. Sustained glycemic control (reduction of HbA1c by about 1%) and weight loss continues with long-term therapy (>5 kg in 2-3 yr) with exetanide97,106,108. No ethnic differences were found in the efficacy and safety of exenatide110. Since metformin has been found to inhibit DPP-4 activity114, addition of metformin to the antidiabetic regimen would enhance the beneficial effects of GLP-1 analogs. The use of exenatide with meglitinides and α-glucosidase inhibitors has not been studied. Exenatide is administered (510g) twice daily subcutaneously (s.c.) before or within 60

Table 4. Clinical studies with liraglutide Dose of Reference liraglutide (LIRA)

Study Other Change Duration treatment in HbA1c (wk)

Seino131

LIRA-0.5-0.9 mg/d

226

Diet

- 1.7%

- 46

Madsbad133

LIRA- 0.225-0.450 mg/d.

193

Diet

- 0.2% to 0.5%

- 14 to - 23

- 0.7 to -1.

Diet

- 0.5%

- 22 to - 34

- 0.3 to -0.4

Diet

+ 0.2%

+ 13

Glimepiride

Harder134

LIRA 0.6 mg/d

Placebo

Vilsbøll

LIRA-0.6 mg/d

LIRA-1.2 mg/d

Garber

LIRA-1.2 mg/d

LIRA 1.8 mg/d

Glimepiride 8 mg/d

Feinglos130

LIRA-0.225 mg/d

LIRA-0.450 mg/d

LIRA-0.600 mg/d

LIRA-0.750 mg/d

Placebo

129

135

Nauck

33 165

0.0

Diet

- 0.6%

- 38

+1.0

Diet

- 0.3%

- 5

- 0.7

Diet

+ 0.5%

+ 5

- 0.9

Diet

- 1.0%

- 36

+ 0.2

Diet

- 1.4%

- 54

- 0.7

LIRA-1.9 mg/d

Diet

- 1.5%

- 54

- 3.0

Placebo

Diet

+0.2%

+ 5

- 1.8

Diet

- 0.8%

- 15

- 2.0

Diet

- 1.1%

- 26

- 2.5

764

210

Diet

- 0.51%

- 5

+ 1.1

Diet

+ 1.3%

+ 36

- 1.9%

Diet

+ 0.9%

+ 11

- 1.2%

Diet

+ 0.2%

+ 0

- 0.6%

Diet

+ 0.3%

+ 16

- 0.9%

Metformin

+ 0.1%

- 4

- 0.6%

52 12

LIRA-0.5-2.0 mg/d

144

Metformin + SU

- 0.8%

- 50

- 1.5

Nauck136

LIRA- 0.6 mg/d

1091

Metformin > 1 g/d

- 0.7%

- 20

- 1.8

LIRA- 1.2 mg/d

Metformin > 1 g/d

- 1.0%

- 29

- 2.6

LIRA- 1.8 mg/d

Metformin > 1 g/d

- 1.0%

- 31

- 2.8

Glimepiride 4 mg/d

Metformin > 1 g/d

+ 0.1%

- 23

+ 1.0

132

Marre

Glimepiride 2-4 mg/d

- 1.1%

- 31

- 0.2

Rosiglitazone 4 mg/d

Glimepiride 2-4 mg/d

- 0.4%

- 18

+ 2.1

Placebo

Glimepiride 2-4 mg/d

+ 0.2%

+ 16

- 2.0

Russell-Jones139

LIRA-1.8 mg/d

Metformin + glimepiride

- 1.3%

-1.8

137

LIRA-1.2-1.8 mg/d

1041

Placebo

Buse111

LIRA-1.8 mg/d

EX-10 ug b.i.d.

464

Metformin + glimepiride

- 0.2%

Metformin + SU

- 1.1%

- 29

- 3.2

Metformin + SU

- 0.8%

- 11

- 2 .9

Wk = week; b.i.d. = twice a day; t.i.d. = three-times a day; d = day; FPG = fasting plasma glucose levels; SU = sulfonylurea; LIRA = liraglutide; EX = exenatide. For glucose levels, to convert mg/dL to mmol/L divide by 18

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Change in Weight (kg)

Diabetes

LIRA- 0.60-0.75 mg/d.

Change in FPG (mg/dL)

min of the morning and evening meals95,96. Unlike sulfonylureas and meglitinides, exenatide increases insulin synthesis and secretion only in the presence of glucose, lessening the risk of hypoglycemia. However, if used in combination with sulfonylureas, exenatide may increase the risk of sulfonylurea-induced hypoglycemia102, and therefore, the dose of sulfonylurea should be decreased if co-administered with exenatide. In patients with normal renal function, doses higher than 2.5g are needed for adequate glycemic response, but in patients with renal dysfunction dose adjustment is required115; it is contraindicated in patients with severe renal impairment. The main adverse effect of exenatide is nausea, which is mild to moderate depending on the dose, and may be transient. However, in some studies, up to 14% patients had to discontinue the drug due to nausea101-103,105. Other gastrointestinal symptoms include dyspepsia, vomiting and diarrhea90. Exenatide may also cause acute pancreatitis116, abdominal pain with or without vomiting, and sometimes renal failure117. In addition to being injected once or twice a day, other drawbacks of exenatide include lack of long-term studies to evaluate sustained efficacy and safety, as well as high cost. The pharmacokinetic and pharmacodynamic profiles of exenatide have been evaluated90,118-121; after a single s.c. injection (5-10 µg), the drug is rapidly absorbed with mean peak plasma levels (tmax) achieved in 1.03.0 hr90. Based on animal studies, the bioavailability of exenatide after s.c. injection has been estimated to be between 65% and 75%90. The mean apparent volume of distribution (Vd) after administration of a single s.c. dose is 28.3 L.90 Plasma levels decrease with a mean t1/2 of 2.4 hr (range 0.9-4.0 hr)90,118-120. The drug does not accumulate after repeated dosing. No ethnic differences were observed in the pharmacokinetics of exenatide119-121. The t of exenatide is increased in patients with renal dysfunction and it is poorly tolerated in patients with severe renal insufficiency and end-stage renal disease115; doses of 5-10g are unsuitable in such patients. The drug is eliminated predominantly by glomerular filtration followed by proteolytic degradation90. There are no significant pharmacokinetic interactions of exenatide with warfarin121, digoxin122, lisinopril123, and lovastatin124.

GLP-1 analogs with long duration of action A long-acting-release (LAR) formula of exenatide, which is to be injected once a week is under development. Initial trials have shown that the LAR formulation is approximately twice as effective as the original twice-daily injectable form, with a similar safety profile but with rate of nausea rates and greater weight loss112,113,125,126. Exenatide LAR injection (in doses of 0.8-2.0mg), administered onceweekly for 15 weeks with or without metformin, reduced HbA1c by 1.4-1.7%113. In a 30-week study, exenatide LAR (2.0 mg) once weekly was found to be superior to exenatide (10 g) twice daily (Table 3) in terms of glycemic control (HbA1c of 6.4% versus 6.8%) and the number

of T2DM patients achieving HbA1c of <7.0% (77% versus 61%)112,113. Adverse effects of exenatide-LAR include nausea, gastroenteritis and hypoglycemia113,114. Several other long-acting analogs of GLP-1 such as liraglutide (NN2211; Victoza®) and albiglutide (naliglutide, GSK716155, Albugon®, Syncria®), are being developed for the treatment of T2DM. Liraglutide is a 30-amino acid peptide attached to a fatty acid molecule and then bonded to albumin (Table 2)127,128; it has 97% homology with GLP-1128. After s.c. administration, the drug is released slowly into circulation (tmax = 9-13 hr), and then cleared slowly (t½of 11-15 hr) and excreted by the kidney127,128. The duration of action is about 24-hr, allowing once-daily s.c. dosing, which effectively reduces fasting as well as postprandial hyperglycemia (12 hr after administration) (Table 5) by increasing insulin secretion, delaying gastric emptying, and suppressing prandial glucagon secretion127,128. Liraglutide administration (0.9 mg/day for 14 weeks) resulted in 75% of patients achieving HbA1c <7.0% and 57% achieving HbA1c <6.5%129, and once daily administration (0.75-2 mg for 5-12 weeks) caused significant improvement in glycemic control (HbA1c reduction of 0.8-1.9%) and a weight loss of up to 3.0 kg128,130, as compared to placebo or glimepiride131; liraglutide administration also decreased appetite causing minimal side effects (nausea, vomiting, and diarrhea) with negligible risk of hypoglycemia128. The clinical efficacy of liraglutide, given as monotherapy or in combination with other antidiabetic drugs, has been amply demonstrated in a large number of clinical trials including the Liraglutide Effect and Action in Diabetes series (LEAD-1 to -6) of studies in more than 4400 T2DM patients (Table 6)111,127-141. In addition to robust glycemic control, liraglutide reduced weight in most patients, improved beta-cell function, lowered blood pressure and triglycerides, and was well tolerated with minimal risk of hypoglycemia; addition of liraglutide to oral antidiabetic regimen improved glycemic control128,129,139,140. A once-aday s.c. injection may be sufficient in normal use. Dosage adjustment may not be required in patients with renal impairment142. In some populations, especially at higher doses, liraglutide decreases body weight111,129,131,134,136,138. Some studies suggest that the efficacy and tolerability of liraglutide administered once-a-day is comparable or even better than exenatide given twice-a-day94,111. An ethnic difference in the effects of liraglutide was observed, in that in Japanese T2DM patients given half the dose of the Caucasian patients, the reduction in HbA1c was more prominent, suggesting that liraglutide may be more effective in Asian than in Caucasian patients possibly due to their improvement of early phase insulin secretion143. The main adverse effects of liraglutide include nausea, vomiting and diarrhea128,135-137. The US-FDA advisory includes the risk of developing pancreatitis and papillary thyroid tumors144,145. After s.c. administration of 1.0 mg of liraglutide in healthy individuals, Cmax of 15-20 nmol/L was obtained at tmax of 12-14 hr; plasma t of liraglutide

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Table 5. Clinical studies with Sitagliptin

Aschner185

SITA -100 mg/d

SITA -200 mg/d

Placebo

741

Change in HbA1c

Change in Change in FPG (mg/dL) Weight (kg)

Diet

- 0.79%

- 13 to 18

- 0.2

Diet

- 0.94%

- 16 to 22

- 0.1

Diet

+ 0.18%

+ 5

- 1.1

Diet

- 0.48%

- 13

- 0.2

Raz

SITA -100 mg/d

SITA -200 mg/d

Diet

- 0.36%

- 11

- 0.6

Placebo

Diet

+ 0.12%

+ 7

- 0.7

203

521

Other treatment

Hanefield191

SITA - 25-50 mg b.i.d./q.d.

555

Diet

- 0.4 to -0.6%

Nonaka205

SITA - 50 mg b.i.d.

151

Diet + exercise

- 1.3%

- 49

SITA - 100 mg q.d.

Diet + exercise

- 0.8%

- 41

Placebo

Diet + exercise

- 0.2%

- 7

Metformin (>1500 mg/d)

- 0.67%

- 16

- 0.6

Metformin (>1500 mg/d)

- 0.02%

+ 9

- 0.7

Pioglitazone 30-45 mg/d

- 0.85%

- 16

+1.8

Pioglitazone 30-45 mg/d

- 0.15%

Diet + exercise

- 0.4% to -0.8%

211

Charbonnel

SITA -100 mg/d

701

Placebo

Rosenstock212

SITA -100 mg/d

353

-11 to -17

Placebo

Scott200

SITA - 12.5 – 50 mg b.i.d.

Glipizide (5-20 mg/d)

Diet + exercise

- 0.76% to -1.38% + 23

Placebo

Diet + exercise

+ 0.23%

+ 8

1172 52

Metformin > 1500 mg/d

- 0.67%

- 10

- 1.5

Metformin > 1500 mg/d

- 0.67%

- 8

+1.1

Metformin > 1500 mg/d

- 22

Nauck

SITA -100 mg/d

Glipizide (5-20 mg/d)

Brazg214

SITA - 100 mg/d

215

Placebo

Goldstein216

SITA- 100 mg/d

SITA- 50 mg/d

SITA- 50 mg/d.

Hermansen

743

+1.5

-13 to -18

+ 0.1 to +0.4

Metformin > 1500 mg/d

- 7

Diet + exercise

- 0.83%

- 23

Metformin 1000 mg/d + Diet

- 1.5%

- 53

Metformin 2000 mg/d + Diet

- 2.07%

- 70

Placebo

Metformin 1000 mg/d + Diet

- 0.99%

- 33

Placebo

Metformin 1000 mg/d + Diet

- 1.3%

- 35

Placebo

Diet + exercise

+ 17%

+ 6

1091 24

Glimepiride

- 0.30%

- 2

+1.1

SITA -100 mg/d

Glimepiride/Metformin

- 0.59%

- 7

+ 0.4

Placebo

Glimepiride

+ 0.27%

+ 18

Placebo

Glimepiride/Metformin

+ 0.30%

+ 12

- 0.7

Scott213

217

SITA -100 mg/d

273

Metformin >1500 mg/d.

- 0.7%

- 11

- 0.4

Metformin >1500 mg/d.

- 0.8%

- 23

+ 1.5

Placebo

Metformin >1500 mg/d

- 0.2%

- 54

- 0.8

Mohan

SITA -100 mg/d

Roziglitazone 8 mg/d

Placebo

218

Roziglitazone 8 mg/d

441

Metformin 1500 mg/d.

- 1.0%

- 31

Metformin 1500 mg/d

- 0.8%

- 23

+ 1.5

Metformin 1500 mg/d.

- 0.2%

- 54

- 0.8

Wk = week; b.i.d. = twice a day; t.i.d. = three-times a day; d = day; N = number of patients in the study; d = per day; FPG = fasting plasma glucose levels; SU = sulfonylurea; for glucose levels, to convert mg/dL to mmol/L divide by 18

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Study Duration (wk)

Diabetes

Dose of Reference sitagliptin (SITA) N

was 11-15 hr146. There is no effect of age or gender on the pharmacokinetics of liraglutide146. Liraglutide is being considered for approval by the US-FDA in 2009. Another drug of this class, albiglutide, a recombinant human GLP-1-albumin-fusion protein (genetic fusion of a DPP-4-resistant GLP-1 dimer to human albumin) has a long duration of action (t½= 6-8 days) and is to be injected every 5-8 days to control hyperglycemia147,148. In (Table 5) addition to controlling blood sugar, it also suppresses appetite. In T2DM patients, albiglutide (16-64 mg given by s.c. injection) improved fasting plasma glucose and postprandial glucose with a low adverse effect profile (mainly, headache, nausea and flatulence)147,148. After injection, albiglutide is readily absorbed but tmax is reached in 3-5 days and its plasma t is between 6 and 8 days147,148.

cagon- and adrenergic-receptor mediated lipolysis.23,55 Thus, GIP promotes energy storage and reduces insulin at the adipocyte level while it stimulates insulin secretion from the β-cells. Hence, there is interest in developing GIP receptor agonist for the treatment of obesity and insulin resistance.55 Although, several GIP analogs have been synthesized, no human studies with GIP analogs have been reported.

Although, the GLP-1 receptor agonists (incretin mimetics) are effective in reducing HbA1c and post-prandial glucose in patients failing sulphonylurea and/or metformin therapy, the role of these drugs in the treatment of T2DM is still debated. An earlier consensus algorithm of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)149, http:// www.eje-online.org/cgi/content/full/160/6/909 - BIB4 suggested to limit the use of GLP-1 receptor agonists only to some specific cases, without considering those agents as the main-line drugs. The reasons for this exclusion were their perceived limited efficacy in decreasing HbA1c in comparison with other agents, their poorly defined safety profile, and their cost94. However, the newer Consensus algorithm issued by ADA/EASD suggests that GLP-1 receptor agonists can be used, in selected cases, as an add-on treatment to metformin150.

Pleiotropic effects of incretins and incretin-mimetics The incretins have a number of pleiotropic (extrapancreatic) actions which have therapeutic benefits beyond controlling hyperglycemia20,21,151-153. As mentioned earlier, GLP-1 and exenatide delay gastric emptying, suppress appetite and cause satiety by central mechanism(s), which translates into reduction in body weight. GLP-1, exenatide and liraglutide have been shown to increase insulin sensitivity and β-cell function (Table 3)111,128,135,139,140,154156 In animal experiments, both exenatide and liraglutide increased β-cell mass, by increasing proliferation and neogenesis and reduction in apoptosis 27,38,157-159; it is not known if these effect on β-cells are also applicable to humans. GLP-1 and analogs regulate cell proliferation and apoptosis in various tissues (such as pancreas, gut and the CNS)158. Exenatide also improves lipid profile (decrease in total cholesterol, LDL-cholesterol and triglycerides, apo B, and an increase in HDL-cholesterol)100. Liraglutide administration also decreases triglyceride levels111,128. Furthermore, exenatide treatment in patients with the metabolic syndrome produced significant improvement in cardiometabolic risk factors and anthropometric parameters160. Since exendin-4 was shown to reverse hepatic steatosis in ob/ob mice161, the GLP-1 mimetics may be a therapeutic option for (human) hepatic steatosis162.

GIP analogs and GIP receptor antagonists In addition to the insulinotropic action of GIP on the pancreatic β-cell, GIP also has been shown to stimulate β-cell proliferation and inhibit apoptosis in islet cell lines. Additionally, functional GIP receptors have been identified on adipocytes, which have been shown to stimulate glucose transport, increase fatty acid synthesis, and stimulate lipoprotein lipase activity in animal models. Thus, there is some interest in GIP analogs as novel therapeutic option for the treatment of T2DM. However, there are several limitations to using GIP itself as a therapeutic agent: a) GIP (1-42) has a short biological t in the circulation due to rapid cleavage and degradation by DPP-4, b) the cleaved metabolite (GIP 3-42) (Table 2) is not only inactive but may also function as a GIP receptor antagonist in vivo, c) clinical GIP infusion studies in T2DM patients have resulted in blunted insulin responses, since GIP no longer modulates glucose-dependent insulin secretion in T2DM even at supraphysiological plasma levels.22 However, the interaction of GIP with its functional receptor on adipocytes results in a) increase in lipoprotein lipase, b) stimulation of lipogenesis, c) enhancement of fatty acid and glucose uptake, d) augmentation of insulin-mediated fatty acid incorporation, and e) inhibition of both glu-

Activation of GLP-1 receptors by GLP-1 in the endothelium, and cardiac and vascular myocytes, has been shown to increase levels of cAMP and cGMP resulting in vasodilation, enhanced coronary blood flow, and increased functional recovery and cardiomyocyte viability after ischemia-reperfusion injury in experimental studies163,164. Exenatide has also been reported to prevent ischemicreperfusion injury in experimental animal models165. It is possible that the incretins and incretin-mimetics may protect the heart against ischemia-reperfusion injury in humans. The central action of GLP-1 also contributes to central regulation of metabolic and cardiovascular homeostasis155, GLP-1 decreases BP and increases myocardial contractility151, and in heart failure patients, infusion of GLP-1 improves endothelial function and symptoms of heart failure43,159,166,167. Some of these beneficial effects are mediated via a nitric oxide synthase-requiring mechanism that is independent of the interaction of GLP-1 with its receptor168. Exenatide decreased both the systolic and diastolic BP in patients following 82-week treatment, probably as a secondary consequence of improvements in blood levels of glucose and lipids and a reduction in body weight97. In other short term (24-week)95 and long term (82-week)107 studies, exenatide (5-10g bid) lowered

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Table 3. Clinical studies with exenatide and exenatide LAR

232

Study Other Change Change Change in Duration treatment in HbA1c in FPG Weight (kg) (wk) (mg/dL)

Moretto95

EX- 5 µg b.i.d.

Diet/exercise

- 0.7%

- 18

- 2.8

EX-10 ug b.i.d.

Diet/exercise

- 0.9%

- 19

- 3.1

Placebo

Diet/exercise

- 0.2%

- 5

- 1.4

Nelson96

EX-10 µg b.i.d.

Diet/exercise

- 0.4%

- 36

---

Placebo

Diet/exercise

+ 0.2%

+ 11

---

Diet/metformin

- 0.9%

Diet/exercise

- 1.0%

Nelson

EX-10 µg b.i.d./20 q.d.

EX-10 ug b.i.d./20 q.d.

Fineman88

EX-0.08 µg b.i.d./t.i.d.

109

SU + Metformin

- 1.0- -1.1%

---

Placebo

SU + Metformin

- 0.3%

---

Ratner97

EX-10 µg b.i.d.

Metformin

- 1.3%

- 31

5.3

Poon98

EX-5 µg b.i.d.

Ex-10 ug b.i.d.

Placebo

Barnett99

Ex-10 ug b.i.d.

127

- 4.3 - 3.7 ---

156

Diet/exercise/metformin - 0.4%

- 20

- 1.4

Diet/exercise/metformin - 0.5%

- 17

- 1.8

Diet/exercise/metformin + 0.1%

+ 7

Metformin/SU

- 1.4%

- 52

- 2.2

Insulin glargine

Metformin/SU

- 1.4%

- 74

+2.3

Klonoff

EX-5-10 ug b.i.d.

Metformin + SU

- 1.0%

Placebo.

Metformin + SU

- 0.4%

- 0.2

- 0.1

Monami94

EX-5-10 ug b.i.d.

Metformin + SU

- 1.2%

- 1.3

- 1.2

Placebo.

Metformin + SU

- 0.4%

- 0.2

- 0.1

deFronzo101

EX- 5µg b.i.d.

Metformin (1000 mg/d)

- 0.4%

- 7

- 1.6

EX-10 µg b.i.d.

Metformin (1000 mg/d)

- 0.8%

- 11

- 2.8

Placebo

Metformin (1000 mg/d)

+ 0.2%

+14

- 0.3

Buse102

Ex- 5 µg b.i.d.

Glimepiride (4 mg/d)

- 0.5%

- 5

- 0.9

EX-10 µg b.id

Glimepiride (4 mg/d)

- 0.9%

- 11

- 1.6

100

138 217 466

336

377

- 5.3

Placebo

Glimepiride (4 mg/d)

+ 0.1%

+ 7

- 0.6

Kendall103

EX-5 µg b.i.d.

Metformin + SU

- 0.6%

- 9

- 1.6

EX-10 µg b.i.d.

Metformin + SU

- 0.8%

- 11

- 1.6

Placebo

Metformin + SU

+ 0.2%

+14

- 0.9

Zinman104

EX-10 µg b.i.d.

Metformin + TZD

- 0.9%

- 29

- 1.8

Placebo

Metformin + TZD

+ 0.1%

+ 2

- 0.2

Heine105

EX-10 µg

Metformin + SU

- 1.1%

- 26

- 2.3

Insulin glargine

Metformin + SU

- 1.1%

- 52

+1.8

733 233 551

Nauck106

EX-10 µg b.i.d.

Biphasic insulin

501

Metformin + SU

- 1.0%

- 32

- 2.5

Metfromin + SU

- 0.9%

- 31

+ 2.9

Blonde107

EX-5-10 µg b.i.d.

314

Metformin + SU

- 1.1%

- 4.4

EX-5-10 µg b.i.d.

551

Metformin + SU

- 0.9%

- 3.5

Buse108

EX-5-10 µg b.i.d.

283

Metformin + SU

- 0.9%

- 2.1

EX-5-10 µg b.i.d.

Metformin + SU

- 1.1%

Brodows109

EX-5-10 µg b.i.d.

314

Metformin + SU

- 0.7% to -0.9%

- 18

- 2.8 to -3.1

Gao

EX-5-10 ug b.i.d.

466

Metformin + SU

- 1.2%

- 1.3

- 1.2

Placebo.

Metformin + SU

- 0.4%

- 0.2

- 0.1

Buse111

EX-10 ug b.i.d.

Metformin + SU

- 0.8%

- 11

- 2.9

Liraglutide 1.8 mg/d

Metformin + SU

- 1.1%

- 29

- 3.2

Drucker112

EX-10 µg b.i.d.

Metformin + SU

- 1.5%

- 25

- 3.8 - 4.3

110

464 295

EX-LAR 2.0 mg/wk

Kim113

EX-LAR 0.8 mg/wk

- 4.7

Metformin + SU

- 1.9%

- 41

Metformin/diet/exercise - 1.4%

- 43

0.0

EX-LAR 2.0 mg/wk

Metformin/diet/exercise - 1.7%

- 40

- 3.8

Placebo

Metformin/diet/exercise + 0.4%

+18

0.0

Wk = week; b.i.d. = twice a day; t.i.d. = three-times a day; d = day; EX = exenatide; EX-LAR = Long-acting exenatide; FPG = fasting plasma glucose levels; SU = sulfonylurea; TZD = thiazolinedione. For glucose levels, to convert mg/dL to mmol/L divide by 18

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Diabetes

Dose of Reference exenatide (EX)

BP, which was independent of weight loss. Liraglutide administration also decreased systolic BP128,129, which occurs even before the weight loss. Exenatide treatment has been shown to prevent early diabetic retinopathy in experimental animals169. The incretins may also be involved in the regulation of taste function, since GLP-1 signaling in taste buds modulates taste sensitivity170. The apparent ability of exendin-4 (exenatide) to arrest progression of, or even reverse nigral lesions once established, normalize dopamine imbalance, and increase the number of cells positive for markers of dopaminergic neurons in the substantia nigra in a model of Parkinson’s disease suggests that pharmacological manipulation of the GLP-1 receptor system could be of therapeutic value in Parkinson’s disease171,172. Furthermore, GLP-1 has been shown to decrease endogenous amyloid-beta peptide (Abeta) levels and protect hippocampal neurons from death induced by Abeta and iron173; these observations suggest that GLP-1 and analogs may be useful in the therapy of Alzheimer’s disease174,175. Since, exenatide potently decreases ghrelin levels in fasting rats, incretin-mimetics could offer a therapeutic option for syndromes characterized by substantial amounts of circulating ghrelin176. Additionally, exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of Huntington’s disease177. It is expected that other GLP-1-receptor agonists and inhibitors of DPP-4 will have some of the above mentioned pleiotropic effects of GLP-1 and agonists.

Dipeptidyl-peptidase-4 inhibitors - incretin enhancers Since the incretin-mimetics have to be given subcutaneously, efforts to find orally active compounds that enhance the endogenous incretin effect, have resulted in the development of inhibitors of DPP-471,76,78,79,84, the enzyme which rapidly inactivates the endogenous incretins. DPP-4, a serine protease/peptidase, involved in many important processes related to nutrition, excretion and immune function (such as maintaining lymphocyte composition and memory T cell generation), is present in many tissues of the body but mostly in the kidney178,179. Serum levels of DPP-4 have been shown to increase with prolonged hyperglycemia180, and its levels decrease with normalization of blood glucose. Increased levels of DPP4 could contribute to the reduction in circulating active GLP-1 and to the consequent postprandial hyperglycemia in T2DM patients with poor metabolic control180. Inhibitors of DPP-4, called the gliptins, block the active site of DPP-4 and thereby prevent the inactivation of incretins, thus prolonging the duration of action of GLP-1 and GIP181. These “incretin enhancers” increase postprandial insulin secretion, effectively improve glycemic control (reduce HbA1c), suppress glucagon release and endogenous glucose production (in the liver), and improve islet cell function (increased β-cell sensitivity to glucose), without a significant effect on gastric motil-

ity or body weight57,80,82,182-199. The DPP-4 inhibitors are more effective in patients with significant residual β-cell function as compared to those with long-standing insulin deficiency. The data on the effect of gliptins on appetite and body weight are not consistent in that some investigators claim that gliptins do not have any effect on these parameters57,58,63,75,76,200,201, while others indicate that the gliptins have a modest effect on appetite (slowing gastric motility and inducing a feeling of satiety) and reduction in body weight189,202,203. Preclinical studies have demonstrated that an approximately 80% inhibition of DPP-4 activity is necessary to achieve a near-maximal effect on glucose concentration204. In humans, 80-88% inhibition is achieved with DPP-4 inhibitors given at the therapeutic doses182,192,205,206, which results in significant rise in GLP-1 and GIP levels192,197. If animal studies turn out to be applicable to man, chronic treatment with DPP-4 inhibitors may prevent the decline in β-cell function and increase basal GLP-1 levels207. Interestingly, the observation that atorvastatin inhibits DPP-4208 suggests that the statin may offer clinical benefit in treating T2DM patients with dyslipidemia. In general, the DPP-4 inhibitors are well tolerated and the risk of hypoglycemia is low when used as monotherapy or in combination with metformin or TZDs. In addition, these drugs have a low gastrointestinal side effect profile and drug administration does not require injection, thus enhancing patient compliance. However, the risk of nasopharyngitis, urinary tract infection and upper respiratory infection increases with the use of these drugs56,71,189. The effect of inhibition of DPP-4 could potentially have some adverse consequences, since DPP-4 has a large number of physiological (endogenous) substrates, and DPP-4 has been implicated in the control of lymphocyte and immune function, cell migration, viral entry, cancer metastasis, and inflammation71. It is possible that inhibition of neuropeptides, other closely related serine proteases such as DPP-2, DPP-8, DPP-9, fibroblast activation protein-alpha/seprase, prolyl endopeptidase, and tryptase may account for the occasional anemia, thrombocytopenia, neurogenic inflammation, allergic reactions, hypertension and splenomegaly that have been reported with certain non-selective DPP-4 inhibitors177,178,209. However, no such adverse effects have been reported in humans with short-term (12 months) use of the approved selective inhibitors at the therapeutic doses81. On the other hand, the DPP-4 inhibitors may be useful to decrease liver inflammation and steatosis, in conditions in which DPP-4 levels are high210. However, the durability and long-term safety of these drugs remains to be determined. Sitagliptin (MK-0431, Januvia®) has been approved (2006) in the USA, and vildagliptin (LAF 237, Galvus®) in Europe (2008), as oral antidiabetic agents, to be used either as monotherapy in T2DM patients inadequately controlled with diet and exercise, or as add-on therapy in combination with metformin, TZDs, or insulin, who have failed oral agents73,185,190, 194. If used as monotherapy, sitagliptin is re-

Sitagliptin may cause gastrointestinal side effects, nasopharyngitis, upper respiratory infection and headache57; cases of severe idiosyncratic hepatotoxicity have also been reported63. Since, sitagliptin is highly selective for DPP-4 and shows little interaction with other proteas (Table 6) es or closely related enzymes, in particular DPP-8 and DPP-9, it is not associated with multiorgan toxicities exhibited by inhibitors of DPP-8/DPP-9 in animal studies209. Never-the-less, another DPP-4 inhibitor, vildagliptin, has been reported to cause skin lesions and kidney impairment in animals, but, no such adverse effects have been reported with short-term (12 months) use of sitagliptin or vildagliptin at therapeutic doses81. Some drawbacks of using sitagliptin include a lack of long-term safety and efficacy data, as well as high cost. After oral administration, sitagliptin is rapidly absorbed (tmax = 1-4 hr), the absorption is not influenced by food intake182,192. The oral bioavailability of sitagliptin is 87%; it exhibits low and reversible binding to plasma proteins (approximately 38%) and is widely distributed in tissues (Vd = 198 L)182,192. The Cmax and AUC are dose-dependent in the 25–400 mg dose range226. Plasma levels decline in a biphasic pattern (t½of the alpha phase = 2-4 hr; terminal t½= 8-14 hr ), independent of the dose182,192. Sitagliptin is mostly excreted (80-87%) by the kidney182,192,227; metabolism by hepatic CYP 3A4 and CYP2C8 accounts for 17% of the administered drug192,227. Pharmacokinetic and pharmacodynamic parameters of sitagliptin are not significantly altered in moderately obese subjects228 or

in diabetic patients192,221. However, pharmacokinetic parameters of sitagliptin are altered in patients with renal insufficiency, with values of Cmax, AUC, and terminal t1/2 increasing with the degree of renal dysfunction: AUC increase 4-5-fold, and Cmax and terminal t1/2 increase 2-fold in patients with end-stage renal disease223,224. The pharmacokinetics of sitagliptin is not significantly affected by mild to moderate hepatic dysfunction.229 Sitagliptin does not alter the pharmacokinetic parameters of glyburide196,230, metformin196,221, rosiglitazone231, simvastatin196,232, warfarin196 or oral contraceptives196. Vildagliptin is used as monotherapy or in combination with metformin, sulfonylureas or TZDs in T2DM patients with inadequate glycemic control following monotherapy; it is also used as monotherapy or in combination with a TZD in patients who cannot tolerate metformin or sulfonylureas194,220. At an oral dose of 100 mg, vildagliptin almost completely inhibits DPP-4 for up to 24 hr233. At least 19 clinical trials have been conducted in more than 7000 randomized patients56-58,65,74,80,82,84; results of some of these studies are presented in Table 6183,188,201,202,235-248. Vildagliptin dose-dependently improves glycemic control in T2DM patients: at doses of 25 to 50 mg b.i.d., the decrease in HbA1c ranges between 0.8% and 1.1%, and fasting glucose levels (by 15 mg/ dL to 30 mg/dL) after monotherapy201,202,234, with further improvement in these parameters when given in combination with metformin188,194,197,198,239,244,246, the effect on weight is minimal237,243,244,246. Vildagliptin is as effective as pioglitazone, and In T2DM patients failing TZD monotherapy, vildagliptin in combination with pioglitazone improved glycemic control240,241,247,249 without additional risk of hypoglycemia240,241. Vildagliptin in combination with metformin, a sulfonylurea or a TZD (given for 2452 wk) not only improved glycemic control in T2DM patients but also appeared to slow the progression of β-cell degeneration187,194,250. Vildagliptin has a low risk of hypoglycemia and is generally well-tolerated at doses of up to and including 200 mg a day in trials lasting up to 52 wk201,251. The drug is also available as a fixed-dose formulation with metformin (Eucreas®)252-254. Vildagliptin improves islet-cell function by increasing both α- and β-cell responsiveness to glucose; improvement in β-cell function (assessed by increase in HOMA-β), insulin sensitivity (reduction in HOMA-insulin resistance), postprandial insulin secretion, and a reduction in postprandial glucagon secretion were observed with vildagliptin (at doses of 25-200 mg/day)75,187,193,194,199,253-264. Vildagliptin improves lipid profile237. After oral administration, vildagliptin is rapidly absorbed giving rise to dose-dependent Cmax (tmax = 1.0-2.0 hr) across the dose range of 25- 200 mg; its oral bioavailability is 85%256,265-268. Food has no effect on the absorption of vildagliptin268. Vildagliptin exhibits low protein binding (9.3%), and it is quickly eliminated (t of ~ 2-3 hr)256,265,266; the t½is dose-dependent (range 1.6-2.5 hr)267-269. There is

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ported to be less effective than sulfonylurea and metformin in lowering HbA1c211. The efficacy of sitagliptin has been demonstrated in least 11 clinical trials conducted in 6781 randomized patients57,59,65,84,185,186,191,195,200,203,205,211,212-220; some data are presented in Table 6. Sitagliptin monotherapy (50-100 mg/day) usually results in a reduction in HbA1c of 0.8-0.9% and glucose levels of 18-22 mg/ dL195,200,203, while addition of metformin211,213,216,219,221 or TZDs212,220 to the antidiabetic regimen improves the efficacy; combination with metformin increases the efficacy in part by the reported inhibition of DPP-4 by metformin114. The drug (at doses of 100-200 mg/d) is well-tolerated in trials lasting up to 52 weeks, and it has a low risk of hypoglycemia57,186,200,203,215,219-222. Sitagliptin may be used as monotherapy in patients who cannot tolerate metformin or sulfonylureas and it may also be used as an alternative to metformin in renal insufficiency57, however, the dose has to be decreased in patients with moderate to severe renal dysfunction or end-stage renal disease223,224. An ethnic difference in the efficacy of the gliptins (sitagliptin and vildagliptin) was observed in that at the same doses, the reduction in HbA1c was 1.5 times higher in Japanese T2DM patients as compared to the Caucasian patients225. Sitagliptin improves β-cell function and decreases insulin resistance157,191,211,214-216. Sitagliptin has a favorable effect on lipid profile (decrease in free fatty acids, triglycerides and increase in HDL-cholesterol)200.

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Table 6. Clinical studies with Vildagliptin Dose of Reference vildagliptin (VILD) Kikuchi 234

VILD â&#x20AC;&#x201C; 25-50 mg b.i.d.

Placebo

Dejager202

VILD - 50 mg q.d.

Pi-Sunyer

Change in FPG (mg/dL)

Diet Diet

+0.1%

- 9

- 0.2

Diet

- 0.8%

- 18

- 1.8

VILD - 50 mg b.i.d

Diet

- 0.8%

- 14

- 0.3

VILD -100 mg q.d.

Diet

- 0.9%

- 14

- 0.8

Placebo

Diet

- 0.3%

- 4

- 1.4 - 0.4

632

Diet

- 0.5%

- 9

VILD - 50 mg b.i.d

Diet

- 0.7%

- 22

VILD -100 mg q.d.

Diet

- 0.8%

- 20

- 0.4

Placebo

Diet

0.0

+ 2

- 1.4

Pan235

VILD - 50 mg b.i.d.

Diet

- 1.4%

- 16

Acarbose 300 mg/d

Diet

- 1.3%

- 27

Schweizer236

VILD - 50 mg b.i.d.

Diet

- 1.0%

- 16

+ 0.3

Diet

- 1.4%

- 31

+ 1.6

Diet

- 0.9%

Diet

- 1.1%

+ 4.7

Metformin 1000 mg b.i.d.

Rosenstock237

VILD - 50 mg b.i.d.

Rosiglitazone 8 mg/d.

Scherbaum238

VILD - 50 mg q.d.

Placebo

Ahren239

VILD - 50 mg q.d.

354

-1.0% to - 1.2%

Change in Weight (kg)

VILD - 50 mg q.d.

291

Study Other Change Duration treatment in HbA1c (wk)

201

660 780 598 306 107

Diet

- 0.2%

- 7

- 0.5

Diet

+0.1%

+ 8

- 0.2

Metformin

- 0.6%

- 18

- 0.4

Metformin

+ 0.1%

+ 4

- 0.5

Diet

- 1.1%

- 23

- 0.6

Placebo

Rosenstock240

VILD -100 mg q.d.

VILD - 50 mg q.d.

Pioglitazone 15 mg q.d. + Diet

- 1.7%

- 43

+ 1.4

VILD -100 mg q.d.

Pioglitazone 30 mg q.d. + Diet

- 1.9%

- 50

+ 2.1

Placebo

Pioglitazone 30 mg q.d. + Diet

- 1.4%

- 34

+ 1.5

Garber241

VILD - 50 mg q.d.

Pioglitazone 45 mg/d.

- 0.8%

- 14

+ 0.1

607

463

VILD - 50 mg b.i.d.

Pioglitazone 45 mg/d.

- 1.0%

- 18

+ 1.3

Placebo

Pioglitazone 45 mg/d

- 0.3%

- 9

+ 1.4

Garber242

VILD - 50 mg q.d.

Glimepiride

- 0.6%

- 5

- 0.1 + 1.3

515

VILD - 50 mg b.i.d.

Glimepiride

- 0.6%

- 7

Placebo

Glimepiride

+ 0.1%

+ 4

- 0.4

Fonseca243

VILD - 50 mg b.i.d.

Insulin 82U/d

- 0.5%

- 14

+ 1.3

Placebo

Insulin 82U/d

- 0.2%

- 4

+ 0.3

296

Bosi

VILD - 50 mg q.d.

Metformin >1500 mg/d

- 0.7%

- 14

- 0.4

VILD - 50 mg b.i.d.

Metformin >1500 mg/d

- 1.1%

- 31

+ 0.2

Placebo

Metformin >1500 mg/d

+0.2%

+ 13

- 1.0

- 47

188

544

Bosi

VILD - 50 mg b.i.d.

1179 24

Metformin 2000 mg/d

- 1.8%

VILD - 50 mg b.i.d.

Metformin 1000 mg/d

- 1.6%

VILD - 50 mg b.i.d.

Diet

- 1.1%

- 27

Placebo

Metformin 2000 mg/d

- 1.4%

- 35

Rosenstock245

VILD - 50 mg b.i.d.

Diet

- 1.1%

- 23

- 0.3

VILD - 50 mg q.d.

Rosiglitazone 8 mg q.d. + Diet

- 1.3%

- 41

+ 1.6

244

Bolli

VILD - 50 mg b.i.d.

Pioglitazone 30 mg q.d.

Goke247

VILD - 50 mg b.i.d.

246

Metformin 2000 mg/d

Ferrannini248

VILD - 50 mg b.i.d.

Glimepiride 4.5 mg/d

786 576 305

0 0 0

Metformin 2000 mg/d

- 0.9%

- 38

+ 0.2

Metformin 2000 mg/d

- 1.0%

- 25

+ 1.9

Diet + pioglitazone

- 1.0%

- 0.5

Diet + pioglitazone

- 1.5%

2789 52

Metformin 2000 mg/d

- 0.44%

- 18

+ 2.5

Metformin 2000 mg/d

- 0.53%

- 21

N = number of patients in the study; b.i.d. = twice a day; q.d. = once a day; d = day; FPG = fasting plasma glucose levels; SU = sulfonylurea; For glucose levels, to convert mg/dL to mmol/L divide by 18

- 0.23

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Conclusions Traditional first-line therapy (sulfonylureas, metformin, TZDs, etc.) might not be appropriate for all T2DM patients. In addition, these drugs have significant adverse effects, such as hypoglycemia and weight gain. The recently developed diabetes therapies based upon GLP-1 receptor agonists (e.g., exenatide, liraglutide) and DPP-4

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Several other DPP-4 inhibitors, including alogliptin (SYR-322)84,274,275,276,277 and saxagliptin (BMS-477118; Onglyza ®)84,275,278,279, etc., are in various stages of development. Both vildagliptin and saxagliptin are apparently close to being approved by the USA-FDA. Monotherapy with alogliptin (12.5-25 mg per day) improved glycemic control (decrease in HbA1c by 0.6%) in T2DM patients without raising the risk of hypoglycemia274,276.280. It appears to be effective and safe in treating T2DM, when added to metformin in patients not sufficiently controlled on metformin monotherapy.281 In addition to metformin, alogliptin can also be combined with TZDs, sulfonylureas and insulin274,277. The drug is well tolerated and has an excellent safety profile, except that hypoglycemia is significant at 800 mg dose282; it appears to be weight neutral. Combination of alogliptin with pioglitazone (in ob/ob mice) increased GLP-1 and insulin levels and reduced glucagon concentration, and exhibited a complementary effect in terms of improved glycemic control and lipid profile283. Never-the-less, studies in diabetic patients are needed to evaluate the long-term safety and efficacy of alogliptin284. After single oral doses (25-800 mg), alogliptin is rapidly absorbed (tmax = 1-2 hr) and is slowly eliminated (t½= 12 – 21 hr). A small fraction of the dose is metabolized (8%), and 60 - 71% of the dose of the drug is eliminated by the renal route282,285. Results of clinical studies with saxagliptin appear to be encouraging, in that a dose-dependent inhibition of DPP-4 is achieved resulting in reduction in HbA1c (by 0.7-0.9%), fasting serum glucose, postprandial glucose levels, with low incidence of adverse effects, and no significant effect on body weight84,275,278, 279,286.

inhibitors (e.g., sitagliptin, vildagliptin) are useful in the management of T2DM because they provide effective reductions in fasting plasma glucose and postprandial glucose levels. In addition, the GLP-1 receptor agonists promote weight loss, whereas the DPP-4 inhibitors are weight neutral, and there is a low risk of symptomatic hypoglycemia. These drugs are effective as monotherapy in drug-naive patients as well as in those in whom other treatments (for example with metformin, sulfonylureas, thiazolinediones, etc.) have been inadequate to achieve glycemic control. When combined with other glucoselowering agents, the GLP-1 receptor agonists and DPP4 inhibitors the efficacy of treatment is increased. These drugs appear to have beneficial effects on β-cell dysfunction, although, the ability of GLP-1 receptor agonists to reduce and/or reverse the progressive β-cell loss remains unclear. Also, it is not known that long-term therapy based upon incretin-mimetics/incretin-enhancers will have sustained benefits, especially in later-stages of the disease; the long-term safety has also not been established. Neverthe-less, the current consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes about the medical management of hyperglycemia in T2DM patients has included GLP-1 receptor agonists as an option when weight loss or risk of hypoglycemia are major considerations. In general, antidiabetic agents should be individualized on the basis of their efficacy as hypoglycemic agents and their extraglycemic effects (on lipids, BP and weight), tolerability and safety, complication of long-term use, ease of drug administration, and costs.

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control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes Obes Metab 2008;10:1047-1056.

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La alimentación

en la genealogía de la diabetes Food genealogy in diabetes

Maryluz Núñez Pacheco1, Ángel Alberto Oroño García1, Rafael Lopez Sanz2, Abdón Toledo3, Maricarmen Chacín3, Edgardo Mengual3, Roberto Áñez3, Valmore Bermúdez Pirela3 y Manuel Velasco4 1 Universidad Bolivariana de Venezuela Sede Zulia. 2 Universidad de Los Andes. 3 Universidad del Zulia. Facultad de Medicina. Centro de Investigaciones Endocrino-Metabólicas “Dr. Félix Gómez”. 4 Unidad de Farmacología Clínica, Escuela de Medicina José María Vargas. Universidad Central de Venezuela, Caracas, Venezuela Dirección de correspondencia: Dra. Maryluz Núñez Pacheco, Universidad Bolivariana Sede Zulia. e-mail: maryluznp@hotmail.com

Aceptado: 25/05/2009

Abstract

Con este artículo se reflexiona sobre la relación entre las ciencias antropológicas y médicas para el estudio del binomio salud-enfermedad y su conexión con los patrones de alimentación de la sociedad humana. Se aborda la Diabetes Mellitus y su relación con la alimentación, tomando en consideración que este último es un factor de riesgo ambiental para el desarrollo de la misma y se ponen de manifiesto elementos genéticos heredables como condicionantes de este mal y la alimentación como un elemento cultural, que pueda ser trasmitida de una generación a otra, en particular, al estar compendiada el mundo complejo de parentesco/genealogía y clase/color. En este sentido, buscamos entre las interpretaciones de los recursos bibliográficos y algunos datos emitidos por nuestros colaboradores, aquellos elementos que pueden ser comunes entre los que padecen la enfermedad y sus patrones de cocina y consumo de alimentos en cada grupo humano afectado. Esto nos brinda la posibilidad de proponer una forma distinta de abordar la enfermedad que nos ocupa, y trabajar desde la perspectiva alimentaria local y regional para el proceso terapéutico, tanto de los diabéticos como de su grupo familiar.

This text begins with reflections about relationships between medical and anthropological sciences with regard to health/sick binomial and its correlation with norms and patrons of the human society. It is approached herewith Diabetes mellitus and its relation with feeding patterns, taking in account environmental risk to develop diabetes Mellitus as a ‘culture’ trait also transmitted through generations as valuable part of kinship/genealogy and class/color complex world. To this, we looked into bibliographical interpretations, data from our informers and colleagues, to obtain shared elements by those who suffer diabetes with their patrons of cook and feeding. Thus, we built a new way to approaching this sickness in order to see it from local-regional ‘culture’, especially its feeding habits, within the therapeutically process which necessarily involves the diabetic persons and the kinship/ genealogical group as well.

Palabras claves: antropología, medicina, diabetes, alimentación, parentesco/genealogía.

Diabetes

Resumen

Internacional

Recibido: 12/04/2009

Key words: anthropology, medicine, diabetes, food, parentless/genealogy.

Introducción La propuesta que se plantea a continuación pretende iniciar el debate en torno a la relación -hasta ahora poco observada- entre la antropología y la necesidad de las ciencias médicas por describir de forma más amplia los elementos que llevan al desarrollo de las enfermedades. En el tema que nos ocupa, la Diabetes Mellitus, existen grandes adelantos científicos, pues se han descubierto algunos determinantes de índole genético (Polimorfismos de un solo nucleótido), que a su vez convergen con factores ambientales que propician estados metabólicos de resistencia a la insulina y disfunción de la célula beta que en conjunto están estrechamente implicados en la fisiopatología de esta enfermedad. Pero en el espectro de todos los fenómenos involucrados en el desarrollo de la Diabetes Mellitus no puede olvidarse que la presencia de factores ambientales vinculados a la alimentación y al sedentarismo son fuertemente partícipes en las transformaciones metabólicas que dan lugar a enfermedad1. Importantes investigaciones indican que una alimentación rica en carbohidratos (especialmente aquellos refinados) puede inducir precozmente el inicio de la enfermedad, más en aquellas personas marcadas con un antecedente familiar de diabetes2 y apuntan que ya el mismo antecedente familiar de diabetes, la obesidad u otra enfermedad metabólica, en conjunción con un nivel de glucosa en ayuno entre 100 y 125,99 mg dL son indicadores de una condición conocida como pre-diabetes3. Sin embargo, es pertinente señalar que no todos los sujetos con factores de riesgo como la obesidad y hábitos de alimentación ¨no saludables¨ desarrollan la enfermedad. Numerosos estudios han concluido en que alrededor de un 20-25% de los individuos obesos son metabólicamente sanos, exhibiendo niveles de lípidos normales e incluso, una sensibilidad a la insulina igualmente en rangos normales, lo que sugiere un posible trasfondo genético protector o tal vez un entorno nutricional menos desfavorable tal como se ha comprobado para aquellas comunidades que consumen una dieta rica en ácidos grasos monoinsaturados (dieta mediterránea, por ejemplo).

A partir de la convergencia entre los estudios sobre la vida social, familiar y clase/color del antropólogo López-Sanz y nuestra experiencia médica en la investigación y tratamiento de la diabetes, hemos vislumbrado otro modo de enfocar este tema. Según autores como Contreras o Fischler, la alimentación es parte vital de un proceso social y cultural marcado por formas específicas de representaciones y prácticas, por lo que a nuestro entender debería explorarse mas seriamente cómo la alimentación es influenciada por la cultura y el ambiente, particularmente en cuanto a las formas de cocina y patrones de consumo que de forma inevitable se trasmiten de una generación a otra, de una manera semejante a como se transmite y

se comparte el sistema de parentesco/genealogía y clase/ color que caracteriza a las sociedades humanas, y en este caso, la venezolana. Aun cuando los funcionalistas insisten marcadamente en el acto mismo de la alimentación y su destino alimentario de “necesidad básica”, ella es en sí todo un proceso complejo tanto metabólico como cultural, así como de “símbolos y significados en contexto”4. Este proceso es de por sí biunívoco y unitario y puede ser representado eficazmente mediante el manejo diestro de la paradoja ‘natura/cultura’, tal y como lo propone la perspectiva teórica y práctica que caracteriza a las ideas de este investigador sobre “parentesco, clase y etnia en Iberoamérica y el Caribe”. No se trata pues del tema de la alimentación vista tradicionalmente atada a una antropología y sociología hijas de la modernidad que no se libera del concepto insulso enmarcado por el término “socio-cultural”, sino que por el contrario, el llamado “hecho culinario” es materia, proceso, símbolo y significado de un factum sapiens-sapiens que es tanto estructura como historia, natura y cultura, por lo que sería un rasgo más complejo que el simple término cocina. Por supuesto, dejar de pensar en la alimentación desde las ciencias médicas, como un simple hecho ambiental; ésta es dueña de una complejidad que como todo arte y ciencia, es actora y creadora de tradición, historia y contemporaneidad. Por lo tanto, insistimos que es importante pensar que desde el punto de vista genético no sólo se pueden trasmitir polimorfismos, sino también las prácticas, costumbres y representaciones de una alimentación con condición y cualidad culinaria particular que podría dar paso a un estado metabólico que puede predisponer a la diabetes3. Como se destaca aquí, se trata de un acercamiento distinto y pertinente a los intentos que algunos profesionales de la medicina procuramos seguir hoy, en la pretensión de concebir una mejor relación con nuestros pacientes, esta vez, con la oportuna ayuda de una antropología actual y crítica con una etnografía para cada situación y contexto de vida humana en la cual “…el trabajo de campo cumple el rol y el despliegue de retórica, disciplina e imaginación necesarios para su avance en el proceso de la obtención de conocimiento coherente y suficiente”5. Consideramos este trabajo, la presentación preliminar de una propuesta de investigación que involucra al campo del parentesco y la genealogía con otro de contexto básico: la vida cotidiana, las creencias y costumbres, los aspectos culturales ligados a los alimentos y su relación con la Diabetes Mellitus y las nacientes disciplinas de la nutrigenómica y la nutrigenética, que sin duda son campos poco atendidos entre nosotros los venezolanos aun cuando se espera iniciar estudios más complejos e interdisciplinarios que bien podrían ser de gran utilidad para una ciencia más cercana a la sociedad con la cual se pretende servir y mejorar.

A través del desarrollo de esta enfermedad, cada uno de los sistemas, aparatos y tejidos comprometidos con los procesos de conducción nerviosa y circulación sanguínea, expresan serio compromiso en su fisiología. Es conocido que sistemas y tejidos como el nervioso periférico, cardiovascular, renal y oftalmológico consiguen en el desarrollo crónico de la enfermedad anomalías serias como el mal funcionamiento metabólico, alteración de su morfología, envejecimiento precoz y hasta de su destrucción. Existe evidencia suficiente que este proceso puede evitarse e incluso, revertirse, con una terapéutica adecuada que incluya un incremento en la actividad física, maniobras nutricionales que disminuyan el consumo de carbohidratos y harinas y tratamiento farmacológico, bien sea con drogas hipoglicemiantes orales y/o insulina. En este sentido, no puede despreciarse el sitial que ocupan los hábitos de alimentación, las preferencias y las costumbres dentro del complejo ambiente que implica el manejo exitoso de la diabetes, tanto en sus aspectos preventivos como curativos. El desarrollo biológico/social de este proceso, conocido como ¨historia natural de la diabetes¨ se inicia alrededor de 10 años antes que la primera manifestación clínica sea evidente o por lo menos perceptible en el paciente o por el médico. La naturaleza aparentemente benigna del inicio y desarrollo de la enfermedad, en especial durante los primero años, pone de manifiesto la poca significación que los afectados le dan a la misma una vez que se reconoce, posiblemente porque al igual que otras enfermedades crónico-degenerativas, como la hipertensión arterial, son asintomáticas o sub-clínicas y obvian tal vez, la principal manifestación clínica de la medicina: el dolor. Sin embargo, cuando la enfermedad se hace consciente, quienes la padecen experimentan cambios físicos que hasta ese momento no se habían reconocido, pero que en muchas ocasiones llevan a la discapacidad física del paciente. Cuando esto último es ya un hecho evaluado médicamente, la discapacidad implica la imposibilidad de desarrollar las actividades personales y sociales diarias, trayendo así secuelas psicológicas profundas en el individuo afectado. Por supuesto, este tipo de patrón es relevantemente característico en la Diabetes mellitus tipo 2 (DM2), de habitual desarrollo en la edad adulta, más no en la diabetes mellitus tipo 1 (DM1), de inicio a tempranas edades de la vida. Pero, precisamente, ambos

tipos de diabetes muestran en común otro hecho más que significativo: la aptitud y la actitud que los grupos de parentesco/genealogía y clase/color muestran en sus hábitos, costumbres y representaciones relativas a la dieta, el cuidado del cuerpo, la salud y estima de la persona. Y es este el dominio que debe ser estudiado o al menos explorado, justamente porque para nosotros, todo desnivel acusado en la compenetración holística en estos sistemas de vida, tendrá sus efectos correspondientes en la bioquímica de la persona, su grupo de pertenencia y su entorno de vida y muerte. Una conciencia más positiva acerca de esta interconexión sistémica podría muy bien ser parte biunívoca de una ingeniería genética posible, que sea capaz, por ejemplo, de colocar un gen humano determinado capaz de mejorar la sensibilidad a la insulina en el hígado o en el tejido muscular, pero también esta conciencia debería llevarnos a aceptar, tal como se tratará adelante, que nuestra genómica a través de miles de años de evolución con nuestro ambiente nos ha programado a ser entidades preparadas a una interacción casi perfecta con una naturaleza que ha sido alterada por nosotros mismos a un punto que los alimentos que comemos (bien en cantidad o en calidad) causan efectos deletéreos en nuestro organismo, y que pueden conducir a enfermedad. Incluso, ya casi se da por supuesto que las personas que siguen un patrón de vida atropellada, agobiante, afectada por la angustia y el stress, es decir, aquellos que siguen un ¨sistema de vida moderno¨ caracterizada por la aceleración, la escasa reflexión y complementado por una alimentación rica en carbohidratos y sedentarismo desarrollarán en algún momento este tipo de procesos morbosos. Por el contrario, hay toda una población que, aún teniendo una carga genética prosiguen una forma de vida plena de actividad física, alimentación alta en fibra y baja en carbohidratos, pero no desarrollan ni ésta y ni otras enfermedades relacionadas de forma temprana. Pues bien, el estudio holístico, médico y antropológico, bien podría iluminar cómo las personas y sus grupos de pertenencia e historia persisten o no en una estrategia de ‘natura’ /´cultura´ de alta pertinencia para la ciencia actual y para una real política de salud personal y pública. En todo caso, se trata de una perspectiva de investigación y creación que demostraría la falsa división entre ciencia, vida y humanidad. Otro ejemplo ayuda a nuestro objetivo principal: Es un hecho que la obesidad constituye un factor de riesgo estrechamente relacionado al desarrollo de la diabetes, y que se hace innegable que genéticamente se han identificado elementos que marcan la transmisión de este tipo de afecciones y que en consecuencia es posible seguir con relativa cercanía cómo se realiza esta transmisión de una generación a otra mediante el estudio de la dinámica propia que rige a los grupos humanos de parentesco/ genealogía. Uno de los motivos por los que se desarrolla este tipo de estudios es el ayudar a precisar cómo la relación parentesco/genealogía de un grupo sostiene relación significativa con su cocina y alimentación distintiva, por

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De la Diabetes Mellitus y su genealogía La Diabetes mellitus (DM) es una enfermedad metabólica muy prevalente que se caracteriza por niveles elevados de glucosa en sangre, bien sea por una falta absoluta en la producción de insulina (Tal como ocurre en la diabetes tipo 1) o por una combinación de resistencia a su acción en conjunción con un trastorno en la secreción de la misma debido a disfunción de la célula beta (tal como se observa en la diabetes tipo 2) que sin el tratamiento adecuado interfiere con el funcionamiento normal de muchos órganos vitales, causando su deterioro3.

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lo que sus dominios atienden en mayor o menor grado de éxito y fracaso a la aparición y el desarrollo de ciertas enfermedades, sean éstas de registro reciente o milenario4. Genes y ambiente, ¿Hacia una definición ecológica de la diabetes mellitus tipo 2? El estudio de la interacción entre genes y el ambiente, en particular, nuestra relación con ciertos tipos de nutrientes se ha incrementado exponencialmente en los últimos 10 años y amenaza con cambiar de forma radical la forma de cómo vemos a los alimentos. La nutrigenómica es la disciplina que estudia la regulación de los genes por la dieta. Desde hace tiempo se conoce como ciertos tipos de compuestos, como los derivados de la Vitamina D y los ácidos grasos poli-insaturados interactúan con los elementos de respuestas a hormonas alterando la tasa de expresión de los genes blanco, regulando así el metabolismo de los carbohidratos, lípidos y proteínas. Más recientemente se ha investigado el uso de isómeros del ácido linoléico con enlaces conjugados dienóicos, que ha demostrado al menos en animales de experimentación su potencial en la reducción de peso y en cambio en la composición corporal6, aunque los resultados en humanos no son del todo claros7-10,11-14.

Más allá de la inducción y represión, la expresión genética puede también modificarse por medio de los llamados cambios epigenéticos, fundamentalmente a través de procesos como la metilación del ADN y la acetilación y metilación de histonas. Así por ejemplo, la inactivación de uno de los cromosomas X en las células somáticas femeninas y el silenciamiento alélico que determina que en ciertos genes que su expresión dependa de si son heredados del padre o la madre, constituyen ejemplos bien conocidos de mecanismos epigenéticos. Por otro lado, muchos estudios epidemiológicos15,16 y en vivo en animales experimentales han demostrado que la malnutrición materna durante la gestación desencadena una serie de adaptaciones metabólicas fetales conocidas como el fenotipo horrador17 que en la edad adulta aumentan el riesgo de desarrollar enfermedades cardiopatía isquémica18-21, HTA22, obesidad23, hiperinsulinemia e hiperleptinemia24 y DM225-27, especialmente en condiciones de sobreoferta de nutrientes28. En este contexto, es interesante la idea de la posibilidad que las interacciones de tipo epigenéticas derivadas de cambios en el patrón de alimentación originen cambios permanentes (programación o imprinting nutricional)29,30, de forma que nuestros actos alimentarios generan cambios genómicos que se expresará a la larga como cambios en el fenotipo tales como el mismo envejecimiento o incremento en la susceptibilidad a padecer neoplasias31 y peor aún, nada garantiza que estas modificaciones en la regulación epigenética puedan sean heredados de generación en generacion29-36, pudiendo explicar el aumento de la prevalencia de las enfermedades crónico degenerativas observadas en el último siglo.

Las modificaciones en la expresión génica que se producen en adipocitos, en el tejido muscular y en hígado implican alteraciones en las diversas rutas metabólicas, en la secreción de adipoquinas y en la capacidad de hiper plasia ocasionada por un sobre-aporte de nutrientes, la hiperglicemia crónica y un incremento en la concentración plasmática de ácidos grasos, en especial, ácido palmítico, sobre lo cual varios autores como Randle y Shulman han establecido las bases moleculares de la resistencia a la insulina y la forma de cómo ciertos metabolitos como las ceramidas pueden conducir a apoptosis de las células beta. Más recientemente, se ha reconocido que la obesidad, el síndrome metabólico y la diabetes mellitus tipo 2 conforman un “cluster” de alteraciones que tienen en común un estado de adiposopatía post-prandial derivada de una capacidad anómala en el almacenamiento de ácidos grasos (disminución de la adipogénesis; incremento de la apoptosis) y un incremento en la síntesis de productos pro-inflamatorios37, que conducen a acumulación ectópica de grasa y modificaciones endocrinas características de los tres estados, es decir, insulinorresistencia e hiperinsulinemia compensadora2,40 y un estado inflamatorio de bajo grado41. En la búsqueda de la curación La realidad y la vida de los afectados por la diabetes es compleja. Por lo general, una vez que reconocen la enfermedad no sólo padecen un estado de mala salud orgánica, sino también acusan el desequilibrio personal y social en el que se perciben involucrados. Es esta situación compleja de vida la que puede interferir su manejo, condicionando muchas veces el desarrollo de esta enfermedad crónica. Y justamente, es esta una situaciónlímite en la que los médicos y las políticas de salud pública deben considerar que la falta de incorporación de los “familiares” o parientes más cercanos y allegados a los procesos de rehabilitación del afectado no hace sino aumentar la brecha, la escisión, entre la terapéutica y la enfermedad misma. Los pasos para el diagnóstico de la enfermedad y su terapéutica incluyen una serie de consideraciones sistematizadas de eventos, en la mayoría de las veces totalmente aisladas a la conciencia social y humana. Vistos como procesos estos pasos casi no se pueden sentir ni ver, sólo se enfocan y producen internamente, en una dirección más fisiológica. Se hacen evidentes una vez que la enfermedad se manifiesta en los cambios físicos que se observan en el paciente, e incluso, en muchas ocasiones, es sólo el médico responsable quien detecte estos cambios y sus correlaciones. Una vez diagnosticada la persona como Diabética, el proceso para su recuperación incluye desde una evaluación psicológica para que el afectado pueda trasformar concientemente su forma de vida, así como su inclusión en un sistema terapéutico que involucra al nutricionista, para adecuar su alimentación a una que disminuya los riesgos de complicaciones metabólicas y las interaccio-

La alimentación como proceso social terapéutico A pesar, que los avances científicos le confieren un gran protagonismo a las características genéticas humanas en el desarrollo de las enfermedades, “la alimentación contemporánea no está sincronizada con nuestros requerimientos genéticos”42. Sin duda, la alimentación humana incluye una dimensión imaginaria, simbólica y social, que otorga un importante valor a los procesos biológicos y sociales de autonomía personal y social43. En la actualidad, los estudios sobre alimentación humana proponen un punto de encuentro entre las teorías nutricionales alimentarias y los marcos de vida y sociedad en los cuales se desarrollan. Es así como nos encontramos frente a la idea de que “ser lo que comemos refleja, la naturaleza compleja y contradictoria del orden social dominante”44, la alimentación como “hecho total”45 participa en gran medida en el desarrollo de algunas enfermedades. Ciertas formas de vida, pueden llevarnos a seguir y concebir variadas formas de alimentación. Por ejemplo, condiciones tecnológicas particulares al momento de procesar los alimentos, hábitos alimentarios descontrolados o frecuentemente intervenidos por complejos esquemas sociales, condicionan un clima propicio para que toda persona, con cierto antecedente genético, desarrolle el desequilibrio metabólico que posteriormente podría llevarlo a padecer la enfermedad de la diabetes, como por ejemplo lo resaltan Vélez y otros46. En un arduo afán por asumir “qué es lo que se debe comer” y “qué es lo que no se debe comer” cuando se padece esta enfermedad, aunado a la necesidad de combinar de forma adecuada los carbohidratos, lípidos y proteínas, para mantener normales los niveles de glucosa en la sangre y detener el daño que produce la DM, muchos profesionales de la medicina excluyen de este proceso consideraciones particulares que el paciente podría aportar a los cambios en su nueva forma de alimentarse, y entonces, como una consecuencia de esto, la alimentación como proceso necesariamente terapéutico no es concebida adecuadamente por el afectado, y la recuperación, en la mayoría de los casos se ve atropellada por las urgencias de medidas médicas como el uso de medicamentos para disminuir los niveles de glicemia. En este sentido, los afectados se vuelven dependientes del uso de los medicamentos y las modificaciones en sus esquema alimenticios no logran los efectos que deberían obtener.

A este descontrol se suma la falta de incorporación los familiares y las personas cercanas a los afectados en el proceso terapéutico, y particularmente a los cambios de hábitos en la alimentación. En este caso de ser un proceso social y vinculante, la alimentación pasa a ser un elemento perturbador y excluyente. Este último efecto contribuye a que los afectados adquieran una cronicidad peculiar que deteriora “su estar” y cambia “su sentir”, hasta el punto de apartarse ellos mismos de lo social y adoptar una nueva conducta ante el final de la vida -como lo diría el poeta y amigo José Javier León-, “no nos preparamos para vivir los instantes que anteceden a la muerte”. En este sentido, es necesario tomar en cuenta -en cualquier esquema terapéutico- que la alimentación es un proceso social, de ‘transcultura’ y que todas las transformaciones que se hagan en función a cambiar los aspectos que pueden agravar la enfermedad del afectado, incluyen los espacios y los valores donde se mueve él y sus “allegados”. Al buen estilo de Kottak, es necesario tomar en consideración que los seres humanos son adaptativos por una condición biológica natural que les permite transformar sus entornos y formas de subsistencia desde procesos netamente biológicos. Participa en un movimiento continuo de relaciones sociales, conductas, acciones que contribuyen a la transformación del propio entorno biológico47. Lo que permite considerar a la antropología como una disciplina de carácter biopsicosocial unidas por una condición común “la cultura”. “La trama de significados” como lo describe Geertz48, permite ver en “la cultura” formas de interpretar el hacer, vivir y convivir de grupos de seres humanos en un mismo territorio, con códigos y tendencias particulares, similares y/o comunes; reflexiones diversas en entornos sociales comunes o acciones comunes en entornos diversos. Estos fenómenos incluyen las artes, la lengua, la economía, las ciencias, la educación y nuestras formas de alimentarnos no están exentas de las formas como se representan las sociedades. No está alejado de la realidad Contreras Hernández, al afirmar que existe una distancia muy estrecha entre la naturaleza y la cultura, en especial cuando hablamos de cómo nos alimentamos44. La selección de los alimentos y las preferencias de gustos y sabores tiene una condición social que interfiere en la funcionalidad del cuerpo humano. Sin embargo, las limitaciones conceptuales hacia las actitudes, las percepciones o las sensaciones, ponen a la biología en un plano casi imperceptible ante el hecho cultural. Nuestra convivencia en el mundo incide sobre nuestros sentidos, a través de los símbolos que nos agrupan. La cocina y el gusto es también historia, como lo diría Le Breton, es la relación entre individuos, es el intercambio de significados, el gusto por los alimentos “es al mismo tiempo conocimiento y afectividad”49.

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nes deletéreas entre algunos nutrientes y el genoma ya antes descrito, a un profesional de la Psicología, capaz de ayudar en la transición difícil que supone aceptar una condición que probablemente le acompañe de por vida, y en general, un equipo médico conformado por especialistas que puedan poner en evidencia condiciones que al ser atacadas precozmente limiten el daño que puedan producir y en consecuencia hagan más fácil y llevadera la rehabilitación.

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Así, el carácter simbólico del hacer en la lengua o la vida cotidiana, tiene sus coincidencias en la memoria, pues a partir de imágenes, olores, sabores, sonidos; se añora, se cuenta, se expresan los recuerdos y estos representan el hacer y sentir de los individuos, las cosas aprehendidas, las no olvidadas aún cuando no sean de la cotidianidad, aún cuando se traigan de la escuela, “cuanto más numerosos son los ritos, las creencias, más determinado es el campo de evocación, más se restringe el abanico de las evocaciones posibles y más son inducidos todos los miembros de una misma cultura a evocaciones semejantes”50. La alimentación puede formar parte de esta palabra aprehendida, evocada que se reproduce en cada nueva generación. La expresión de “somos lo que comemos”51 nos invita a interpretar el comportamiento de los seres humanos a partir de las maneras de combinar sabores y olores, la conducta y la socialización de las personas en el recolección, procesamiento, intercambio y consumo de alimentos. La alimentación es así, un conjunto de relaciones, representaciones, tradiciones y costumbres, símbolos y significados, que se aprehenden entre la cotidianidad de la familia y la comunidad, que pueden ser trasmitidas de una generación a otra entre creencias y prácticas compartidas. La clave de una buena descripción de elementos relacionados con la alimentación en una sociedad determinada, está en reconocer cómo los miembros de un grupo cultural construyen sus tradiciones y expresan sus hábitos de consumo, hasta la sublime condición de formar parte de su identidad. Así, encontramos una gran variedad de combinaciones y secretos que expresan la forma de saborear al mundo, entre especias y mezclas de dulces y salados, agrios y ácidos, que dan a los productos de la naturaleza, animal o vegetal, la sazón y el gusto por combinaciones particulares que nos representan. Algo de esto puede captarse en Fischler, cuando propone que en lugar de preguntamos por qué comemos ciertos alimentos más que otros, deberíamos plantearnos la pregunta de por qué no comemos ciertas sustancias, por qué no consumimos todo lo que es biológicamente comestible. Más en la vía del etnólogo, acota: “El ser humano actúa no sólo atendiendo a los dictámenes de su organismo, sino también de su pensamiento y de sus representaciones”43.

Entonces, dado que la alimentación es parte de eso que llamamos cultura, podemos pensar que las prácticas culinarias pertenecen a eventos que se pueden trasmitir de una a otra generación; pensar que más que una simple predisposición genética marcada por algún elemento que pocos podemos reconocer en nuestras representaciones, los alimentos y las formas de consumirlos pueden identificarnos con rasgos o características observables en cualquier otro personaje de nuestras familias; y que además establecen los pasos previos para

el inicio de una enfermedad -silenciosa para nuestros oídos- acostumbrados a ruidos, estridencias y música ajenos totalmente a los ritmos y armonías del cuerpo de especie homo sapiens sapiens. Identificar estas fortalezas en los grupos humanos (familias) y transformarlas en un hacer común que permita la contraloría de nuestras propias maneras de cocinar e intercambio de conocimientos culinarios, podrían ser el principio del camino por donde andar en la búsqueda de una franca y asertiva incorporación de las multidisciplinas de la promoción de salud y la salud colectiva en el hacer de nuestro mundo contrariado por el estigma de las sociedades de consumo.

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Shulman G. I. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106(2): 171-176 (2000).

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