MXPA01003008A - Use of glp-1 or analogs in treatment of stroke - Google Patents

Abstract

This invention provides a method of reducing mortality and morbidity associated with stroke. GLP-1, a GLP-1 analog, or a GLP-1 derivative, is administered at a dose effective to normalize blood glucose.

Description

USE OF GLUCAGON 1 (GLP-1) OR ANALOGS LIKE PEPTIDE IN THE TREATMENT OF FULMINING CRISIS FIELD OF THE INVENTION The present invention relates to methods and compositions for reducing mortality and morbidity after a fulminating crisis, controlling hyperglycemia. The methods and compositions are particularly useful for diabetics not dependent on insulin, those who are at a new risk of fulminating crisis or who suffer an ongoing or recurrent attack. The preexisting hyperglycemia is healed and the new emergence of hyperglycemia is prevented. BACKGROUND OF THE INVENTION Morbidity and mortality from cardiovascular diseases is higher in patients with overt diabetes or with impaired glucose tolerance compared to patients who do not suffer from these disorders. Diabetics account for 24% of the total number of patients admitted to the coronary care units for suspected myocardial infarction, while these constitute only 5% of the general population (Fuller, 1993). The mortality of diabetic patients in hospital suffering from myocardial infarction is double that of non-diabetic patients (Ha sten, 1994, Malmberg and Rydén, 1988). Diabetics experience more morbidity and Ref: 127683 die more frequently in the post-recovery phase, compared to the other periods; Much of this is due to fatal reinfarction and congestive heart failure (Stone, 1989, Karlson, 1993, Barbash, 1993). The difference in mortality and morbidity between diabetics and non-diabetics after a fulminant seizure persists, despite the reduction in the incidence of morbidity and mortality after acute myocardial infarction (Granger, 1993, Grines, 1993). It is known that the risk of a fulminant crisis is markedly higher in patients with diabetes. Thus, the risk of a fulminant crisis in male patients with non-insulin-dependent diabetes (mellitus) (NIDDM) was approximately three times higher and in women NIDDM five times higher than in the corresponding non-diabetic subjects (Lehto, 1966). In another study in Finland, men with diabetes at the baseline had a sixfold higher risk of death from fulminating seizures, while the relative risk of men who developed diabetes during follow-up was 1.7. In women, the respective relative risks were 8.2 and 3.7 (Tuomilehto, 1996). In addition, another study has shown that also mild and unrecognized hyperglycemia was a risk factor for acute fulminant crisis and that cumulative mortality was elevated in patients with a high blood glucose value, regardless of their HbA_, values that reflect a long-term glycemic control (Gray, 1987). The deteriorating effect of hyperglycemia on the outcome of the fulminant crisis has also been demonstrated in other studies (Cazzato, 1991, Kiers, 1992, deFalco, 1993, Moulin, 1997, Weir, 1997). The intensity of the stress hormone responses during the fulminating crisis contributes significantly to the development of hyperglycemia (O'Neill, 1992), but it is likely that hyperglycemia per se adversely affects ischemic cerebral metabolism, mainly due to prolonged acidosis ( Levine, 1988, Wass and Lanier, 1996). Animal studies strongly support the idea that hyperglycemia significantly aggravates brain damage during a fulminating crisis, due to a reduction in regional cerebral blood flow, marked edema and compression of the brainstem, and an increase in the size of the infarct. , to an increase in systolic ca2 + levels, to an accumulation of lactate, to an interruption of the blood-brain barrier and to an increase in hemorrhage (Duckrow, 1985, 1987, by Courten-Myers, 1988, Silvka, 1991, Araki, 1992, Wagner, 1992, Dietrich, 1993, Broderick, 1995). Palliative measures are needed to normalize blood glucose and control metabolic cascades that exacerbate the damages caused by fulminating seizures in diabetics. These can be achieved by adjusting the infusion of insulin and glucose and the close post-regulation of blood glucose by subcutaneous treatment of multiple-dose insulin. This last regime, when used in the treatment of diabetic patients during acute myocardial infarction, mortality decreases during the year after myocardial infarction by 30%, compared with a control group of diabetics who did not receive insulin treatment unless consider necessary (Malmberg, 1995). However, insulin infusion creates a potential for hypoglycaemia, which is defined as a blood glucose value below 0.3 mM. Hypoglycemia increases the risk of myocardial infarction, ventricular arrhythmia and is a dangerous consequence of insulin infusion. An algorithm for the infusion of insulin for diabetics with fulminating crisis was developed to prevent hypoglycaemia (Hendra, 1992). However, 21% of patients developed hypoglycaemia under this algorithm. In another study of glucose control after myocardial infarction, 18% of patients developed hypoglycemia when they underwent infusion with insulin and glucose (Malmberg, 1994).

- - Insulin infusion also requires frequent monitoring of blood glucose levels, so that the onset of hypoglycaemia can be detected and remedied as soon as possible. In patients who received insulin infusion in the cited study (Malmberg, 1994), blood glucose was measured at least every 2 hours and the infusion rate was adjusted accordingly. Thus, the safety and efficacy of insulin-glucose infusion therapy depends on easy and rapid access to blood glucose data. Such an intense need to monitor blood glucose puts a heavy workload on health professionals and increases. the inconvenience and the cost of the treatment. As a result, intensive care units often do not have the resources to optimize blood glucose levels in diabetics, as could be obtained by intravenous administration of insulin. Considering the risks and workloads inherent in insulin infusion, an alternative approach is needed to manage blood glucose during an acute fulminant crisis. The hormone incretin, which is the glucagon-like peptide 1, abbreviated as GLP-1, is processed from proglucagon in the intestine and intensifies the release of insulin induced by nutrients (Krcymann, 1987).

- - Several truncated forms of GLP-1 are known to stimulate insulin secretion (insulinotropic action) and the formation of cAMP (see, e.g., Mojsov, 1992). A relationship has been established between several in vitro laboratory experiments and the insulinotropic responses of mammals, especially humans, to the exogenous administration of GLP-1, GLP-I (7-36) amide and GLP-I (7-37). ) acid (see, eg, Nauck, 1993 a and b, Gutniak, 1992 and Thorens, 1993). GLP-1 (7-36) amide exerts a pronounced anti-diabetic effect in insulin-dependent diabetics, by stimulating insulin sensitivity and intensifying the release of insulin produced by glucose at physiological concentrations (Gutniak, 1992). When administered to noninsulin-dependent diabetics, GLP-1 (7-36) amide stimulates insulin release, decreases glucagon secretion, inhibits gastric emptying and increases glucose utilization (Nauck, 1993 a and b, Gutniak, 1992). ). The use of GLP-1 type molecules for the prolonged therapy of diabetes has been obstructed because the serum half-life of such peptides is very short. For example, GLP-I (7-37) has a serum half-life of only 3 to 5 minutes. GLP-I (7-36) amide has a half-life of approximately 50 minutes when administered subcutaneously. Thus, these LPG molecules must be administered in the form of a continuous infusion to achieve a controlled effect (Gutniak, 1994). BRIEF DESCRIPTION OF THE INVENTION The present invention provides methods and compositions for reducing mortality and morbidity after a fulminating crisis. The method includes administering a compound from the group consisting of GLP-1, GLP-1 analogs, GLP-1 derivatives and pharmaceutically acceptable salts thereof, at an effective dose to normalize blood glucose, to a patient who I needed it. The present invention provides the benefits of reducing mortality and morbidity in diabetics after a fulminating crisis, for example, by effecting a smaller infarct size. The treatments of the present invention in non-insulin dependent patients compared to the combined treatment with insulin and glucose infusions, avoids the inconvenience and costly frequent monitoring of blood glucose, as well as the interpretation of the blood glucose results and the adjustment of the insulin dose rate. The treatments also avoid the always present risk of hypoglycaemia that accompanies insulin infusion. In the present invention, some GLP-1 have short half-lives and the consequent need for continuous administration is not a disadvantage because the patient is typically in bed, in an intensive care unit, where the fluids are administered continuously parenterally. . This treatment includes all patients with hyperglycemia, regardless of whether they were diagnosed or not as diabetics. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the effect of continuous infusion of GLP-I (7-36) amide on the average concentration of blood glucose (mM), (-___-) in five NIDDM patients at night. The graph also illustrates the effect of continuous insulin infusion on the average blood glucose concentration (or) in the same five NIDDM patients, but on a different night. FIG. 2 is a graph showing the effect of the infusion of GLP-l (7-36) amide on the average concentration of blood glucose (mM) (-__-) in five NIDDM patients when they were infused during the day, for 3 hours starting at the beginning of each of the three meals. The graph also illustrates the effect of subcutaneous insulin injection on the average blood glucose concentration (or) in the same five NIDDM patients, but not on a different day, and with an injection shortly before each meal. DETAILED DESCRIPTION OF THE INVENTION The methods and compositions, in particular medicaments (compositions or pharmaceutical formulations) using the glucagon-like peptide 1, analogs or derivatives thereof, are effective in reducing mortality and morbidity after a fulminant crisis in diabetic patients. , particularly in non-insulin-dependent diabetics. The GLP-1 analogs and derivatives that are useful for the practice of the present invention are those that have a longer half-life compared to GLP-1 and the ability to affect mortality and morbidity when administered to a subject . Fulminant crisis The fulminant crisis or cerebrovascular accident (CVA) is a cerebrovascular disease characterized by the abrupt appearance of a nonconvulsive and focal neurological deficit. The fulminating crisis causes approximately 200,000 deaths in the United States each year, as well as neurological disability. In Western countries, ischemia-infarction causes fulminant attack in approximately 85-90% of cases, while intracranial hemorrhages are found in the rest of the group of patients. Brain ischemia is caused by a reduction in blood flow lasting several seconds.

If the lack of flow lasts more than a few minutes, a heart attack develops into the brain tissue. The most common cause of ischemia and cerebral infarction are atherosclerosis with thromboembolism and cardiogenic embolism. The ischemic fulminating crisis is characterized clinically by its mode of emergence and its subsequent course. Characteristic presentation is an acute picture of hemiparesis in an individual in the atherosclerotic age group. However, any symptoms of brain dysfunction can occur. The signs and symptoms of the disease of the carotid system often affect the distribution of the middle cerebral artery and the patient may exhibit a contralateral hemiparesis, hemisensory deficit and hemopsia. When the dominant hemisphere is involved, there is usually some degree of aphasia. The anterior (carotid) or posterior (vertebrobasilar) circulation may also be involved, which results in more or less specific clinical symptoms. Hyperglycemia is defined as a plasma glucose concentration of approximately 200 mg / dL (11.1 mmol / L) or greater, or a fasting plasma glucose level of 125 mg / dL (7.0 mmol / L or greater). One aspect of the present invention is to prevent hyperglycemia or reduce it to normal values.

Compounds The GLP-1 analogs, derivatives, variants, precursors and homologs are suitable for the practice of the present invention insofar as the active fragment that effects the reduction of mortality or morbidity after the fulminating crisis is included. "GLP-1" means GLP-I (7-37). By custom in the art, the amino-terminal end of GLP-I (7-37) is assigned the number 7 and the carboxyl-terminal end is the number 37. The amino acid sequence of GLP-1 (7-37) ) is known in the art, but is presented below for the convenience of the reader.

Thr-Phe-Thr-Ser-Asp "-Val-Ser-Ser-Tyr-Leu? 0- Glu-GJy-Gln-Ala-Ala ^ -Lys-GJu-Phe-Ile-Ala'0- Trp-Leu Val-Lys-Gl '-Arg-Gly ^ -COOH A "GLP-1 analogue" is defined as a molecule that has a modification that includes one or more amino acid substitutions, deletions, inversions or additions when compared to LPG -1 GLP-1 analogs known in the art, include, for example, GLP-K7-34) and GLP-1 (7-35), GLP-1 (7-36), Val8-GLP-1 (7-37), Gln9-GLP-1 (7-37), D-Gln9 -GLP-1 (7-37), Thrld-Lys18-GLP-1 (7-37) and Lys18-GLP-1 (7-37). The GLP-1 analogs preferred with GLP-1 (7-34) and GLP-1 (7-35), which are described in US Pat. No. 5,118,666 and also GLP-1 (7-36). These compounds are the biologically processed forms of GLP-1 that have insulinotropic properties. Other analogs of GLP-1 are described in US Pat. No. 5,545,618. A "GLP-1 derivative" is defined as a molecule having an amino acid sequence of GLP-1 or a GLP-1 analog, but which additionally has at least one chemical modification of one or more of its side groups. amino acid, carbon atoms, amino-terminal group or carboxyl-terminal group. Chemical modification includes adding chemical entities, creating new links and removing chemical entities. Modifications in the side groups of amino acids include acylation of the e-amino groups of lysine, N-alkylation of arginine, histidine or lysine, alkylation of glutamic acid or aspartic acid and deamination of glutamine or asparagine. Modifications of the amino-terminal end include modifications of deamination, N-lower alkyl, N-lower dialkyl and N-acyl. Modifications of the carboxyl-terminal group include the amide, lower alkylamide, lower dialkylamide and lower alkyl ester. A lower alkyl group is an alkyl group of 1 to 4 carbon atoms. In addition, one or more side groups, or terminal groups, can be protected by protecting groups known to those skilled in the chemistry of proteins. The carbon a of the amino acid can be monomethylated or dimethylated. In the present invention, a preferred group of GLP-1 analogs and derivatives for use in the present invention, is comprised of the various GLP-1 molecules claimed in US Pat. No. 5,545,618. Effective analogues of the active GLP-1 peptides, 7-34, 7-35, 7-36 and 7-37 have amino acid substitutions at positions 7-10 and / or are truncated at the C-terminal end and / or they contain several other amino acid substitutions in the basic peptide. Analogs having D-amino acid substitutions at positions 7 and 8 and / or are N-alkylated or N-acylated at the 7-position, are particularly resistant to degradation in vivo. Analogs that show better insulin stimulatory properties have the native sequence of GLP-1, 7-34, 7-35, 7-36 or 7-37, or the C-terminal amide thereof, in which it was performed when minus one modification that is selected from the group consisting of: (a) substitution of a neutral amino acid, arginine, or a D form of lysine, by lysine at position 26 and / or 34 and / or a neutral amino acid, lysine, or a D form of arginine by arginine at position 36; (b) a substitution of an oxidation-resistant amino acid with tryptophan at position 31; (c) a substitution in accordance with at least one of the following: Y by V in position 16, K by S in position l D by E in position 21, S by G in position 22, R by Q in position 23, R for A at position 24, Q for K at position 26, (using the single-letter codes for amino acids) (d) a substitution comprising at least one of the following: a small neutral amino acid alternative by A in position 8; an alternative acidic or neutral amino acid by E at position 9; an alternative neutral amino acid by G at position 10; and an alternative acidic amino acid by D at position 15; and (e) a substitution of an alternative neutral amino acid or the D or N-acylated or alkylated form of histidine, by histidine in position 7. With respect to the modifications of the clauses (a), (b), (d) and (e), the substituted amino acids may be in the D form. The substituted amino acids in the 7-position may also be the N-acylated or N-alkylated form. Peptides that show greater resistance to degradation in plasma, compared to GLP-1 (7-37) are suitable for the practice of the present invention. In these analogs, any of the above-mentioned truncated forms of GLP-1 (7-34) or GLP-1 (7-37) or their C-terminal amidated forms is modified by (a) a substitution of an amino acid D- neutral or D-acid by H at position H, or (b) a substitution of a D-amino acid by A at position 8, or (c) both, or (d) a substitution of an N-acylated form or N -alkylated from any natural amino acid, by H in position 7. Thus, analogs that are resistant to degradation include (N-acyl (1-6C) AA) 7GLP-1 (7-37) and (N-alkyl) (1-6C AA) 7GLP-1 (7-37), where when AA is a lysyl residue, one or both nitrogens may be alkylated or acylated, AA symbolizes any amino acid consistent with the retention of insulin stimulating activity. substitutions of D-amino acids of positions 7 and 8, residue D of any acidic or neutral amino acid can be used in position 7 and of any amino acid in position 8, new amente consistent with the stimulating activity of insulin. Either or both of the positions 7 and 8 can be substituted with a D-amino acid; the D-amino acid in the 7-position can also be acylated or alkylated. These modified forms are applicable not only to GLP-I (7-37), but also to shorter truncated analogues. Thus, among the preferred analogues are those in which the (7-34), (7-35) or (7-37) form of GLP-1 has been modified only for the substitution of a neutral amino acid, arginine, or a D form of lysine, by lysine at position 26 and / or 34 and / or a neutral amino acid, lysine, or a D form of arginine, by arginine at position 36. Particularly preferred are those wherein the amino acid substituted by lysine at positions 26 and 34 it is selected from the group consisting of K +, G, S, A, L, I, Q, R, R + and M, and by arginine at position 36, it is selected from the group consisting of K, K +, G, S, A, L, I, Q, M and R + (where t indicates a D form). Also preferred are analogs wherein the only modification is the replacement of an oxidation-resistant amino acid by tryptophan at position 31. Particularly preferred substitutions are selected from the group consisting of F, V, L, I, A and Y. Particularly preferred are those analogs in which combined substitutions of S by G have been made at position 22; R of positions 23 and 24 by Q and A respectively, and Q by K in position 26; or substitutions of Y by V in position 16 and K by S in position 18; or these substitutions plus D by E at position 21. Among these analogs, those in which the small neutral amino acid substituted by alanine at position 8 is selected from the group consisting of S, S +, GC, C +, Sar, are particularly preferred. A +, beta-ala and Aib; and / or the acidic or neutral amino acid substituted by glutamic acid at position 9, is selected from the group consisting of E +, D, D +, Cya, T, T +, N, N +, Q, Q +, Cit, MSO and acetyl- K and / or the alternative neutral amino acid substituted by glycine at position 10, is selected from the group consisting of S, S +, Y, Y +, T, T +, N, N +, Q, Q +, Cit, MSO, acetyl-K , F and F +; and / or wherein D is replaced by E at position 15. Analogs are also preferred where only position 7 has been altered. Preferred substitutions are those in which the - - amino acid replacing histidine at position 7 is selected from the group consisting of H +, Y, Y +, F, F +, R, R +, Orn, Orn +, M, M +, N -formyl-H, N-formyl-H +, N-acetyl-H, N-acetyl-H +, N-isopropyl-H, N-isopropyl-H +, N-acetyl-K, N-acetyl-K +, P and P + . Also preferred are those embodiments with a combination of only two of the kinds of modified forms referred to above, in addition to the following specific embodiments (analogs): (Y) 7-GLP-1 (7-37); (N-acetyl-H) 7-GLP-I (7-37); (N-isopropyl-H) 7-GLP-I (7-37); (A +) 8-GLP-I (7-37); (D) 9-GLP-1 (7-37); (D +) 9-GLP-I (7-37); (F +) 10-GLP-I (7-37); (S) 22 (R) 23 (R) 24 (Q) 26-GLP-I (7-37); (s) 8 (Q) 9 (Y) 16 (K) 18 (D) 21-GLP-I (7-37). Preferred forms of analogs with improved stability have also been subjected to only one or at most two amino acid modifications. Preferred substitutions for histidine in the 7-position include the D-forms of amino acid-or-neutral acids of the D-forms of histidines. Preferred are P +, D +, E +, N +, Q +, L +, V +, I + and H +. Histidine in position 7, or a replacement (D or L), it can also be N-alkylated (1-6C) or N-acylated (1-6C). The alkyl groups are straight or branched chain (including cyclic) hydrocarbyl residues with the indicated number of carbon atoms. The acyl groups are of the formula RCO-, wherein R is an alkyl group. Preferred alkyl groups are t-propyl, a-propyl and ethyl; Preferred acyl groups are acetyl and propionyl. Preferred residues that can be alkylated or acylated include P, D, E, N, Q, V, L, I, K and H, either in form D or in form L. Preferred substitutions for alanine in position 8, are D forms of P, V, L, I and A; D-forms of D, E, N, Q, K, T, S and H are also preferred. Some specific analogues show both better insulin stimulating activity and better stability. A preferred group of analogs and derivatives of GLP-1 for use in the present invention, is composed of molecules of the formula: X-Glu-G! Y10- Thr-Phe-T_x-Scr-_v_f, 3-Val-Ser-Ser-Tyr-Leu20-Y-Gly ^ Gln-Ala-Ala ^ -Lys-Z-Phe-Ue-Ala30 - Trp-Lcu-VaJ-Lys-Giy35-Arg-R2 and pharmaceutically acceptable salts thereof, wherein: Ri is selected from the group consisting of L-histidine, D-histidine, desaminohistidine, 2-aminohistidine, β-hydroxyhistidine, homohistidine, alpha-glutromethylhistidine and alpha-methylhistidine; X is selected from the group consisting of Ala, Gly, Val, Thr, lie and alpha-methyl-Ala; And it is selected from the group consisting of Glu, Gln, Ala, Thr, Ser and Gly; Z is selected from the group consisting of Glu, Gln, Ala, Thr, Ser and Gly; and R2 is selected from the group consisting of NH2 and Gly-OH; provided that the compound has an isoelectric point in the range of about 6.0 to about 9.0 and further provided that when Ri is His, X is Ala, Y is Glu and Z is Glu, R2 must be NH. Numerous GLP-1 analogs and derivatives having an isoelectric point in the range of about 6.0 to about 9.0 have been described and include, for example: GLP-1 (7-36) NH2 Gly, -GLP-1 (7-36) NH2 Gln9-G P-l (7-37) D-Gln! > -G P -] (7-37) acetyl-Lys'-G Pl (7-37) T_r9-GLP-1 (7.37) D-Hir ^ -GUM ^?) -GUM (7-37) D-Asn » -GLP-I (7-37) Ser22-Arg ^ -Ai ^ '- Gln8-GLP-1 (7-37) Thr "- ys" -GIJM (7-37) Lys "-GL_M (7-37) Argv -GU > - (7-37) Another preferred group of active compounds for use in the present invention is described in International Publication WO 91/11457 (related to US Patent 5,545,618) and includes GLP-I (7 -34), GLP-1 (7-35), GLP-K7-36) or GLP-1 (7-37) or the amide form thereof, and pharmaceutically acceptable salts thereof, which have undergone at least one modification including those shown below: (a) substitution of a glycine, serine, cysteine, threonine, asparagine, glutamine, tyrosine, alanine, valine, isoleucine, leucine, methionine, phenylalanine, arginine or D-lysine residue by lysine in position 26 and / or in position 34, or the substitution of a - - glycine residue, serine, cysteine, threonine, asparagine, glutamine, tyrosine, lanin, valine, isoleucine, leucine, methionine, phenylalanine, lysine or D-arginine, by arginine at position 36; (b) replacement of an oxidation-resistant amino acid with tryptophan at position 31; (c) the substitution of at least one of the following: tyrosine by valine at position 16; lysine by serine in position 18; aspartic acid by glutamic acid in position 21; serine by glycine in position 22; arginine for glutamine in position 23; arginine for alanine at position 24 and glutamine for lysine at position 26; and (d) substituting at least one of the following: glycine, serine or cysteine for alanine at position 8; aspartic acid, glycine, serine, cysteine, threonine, asparagine, glutamine, tyrosine, alanine, valine, isoleucine, leucine, methionine or phenylalanine by glutamic acid in position 9; serine, cysteine, threonine, asparagine, glutamine, tyrosine, alanine, valine, isoleucine, leucine, methionine or phenylalanine by glycine in position 10; and glutamic acid by aspartic acid in the 15-position; and (e) the substitution of glycine, serine, cysteine, threonine, asparagine, glutamine, tyrosine, alanine, valine, isoleucine, leucine, methionine or phenylalanine, or the D- or N-acylated or alkylated form of histidine, by histidine in position 7; wherein, in the substitutions of subparagraphs (a), (b), (d) and (e), the substituted amino acids may optionally be in the D form and the amino acids substituted in the 7-position may optionally be in the N-form -acilated or N-alkylated. Because the enzyme dipeptidyl-peptidase IV (DPP IV) may be responsible for the rapid in vivo inactivation of GLP-1 administered (Mentlein et al., 1993), the administration of GLP-1 analogs and derivatives are protected from DPP IV activity is preferred, and administration of Gly8-GLP-1 (7-36) NH2, Val8-GLP-1 (7-37) OH, α-methyl-Ala8-GLP is more preferred. -l (7-36) NH2 and Gly8-Gln21-GLP-1 (7-37) OH, Gly8-GLP-1 (7-37) OH or pharmaceutically acceptable salts thereof. The use in the present invention of a molecule in accordance with US Pat. No. 5,188,666 ('666) is also preferred. Such a molecule includes a peptide having one of the following amino acid sequences: NH H¡s7-Ala-GIu-Gly, ° - Thr-Phe-Thr-Scr-Asp ^ -Val-Ser-Ser-Tyr-Leu20- GIu-Gly-G_n-Ala-AlaM-Lys-GJu-Phe- Ue-AlaM- Tip-Leu-Val-X where X can be Lys and Lys-Gly; or a derivative of said peptide, and wherein the peptide can be a pharmaceutically acceptable acid addition salt of said peptide; a pharmaceutically acceptable carboxylate salt of said peptide; a pharmaceutically acceptable lower alkyl ester of said peptide; or a pharmaceutically acceptable amide of said peptide, which is selected from the group consisting of amide, lower alkylamide and lower dialkylamide. The invention of the "666 patent" refers to a peptide fragment that is insulinotropic and is derived from an amino acid sequence of natural origin. These fragments are suitable for the practice of the present invention. The present invention comprises a compound selected from the group consisting of: (A) a peptide comprising the sequence: Hista-Ala-Glu-G] and-T__r-Phe-Thr-Ser-Asp-Val-Ser-Ser -Tt-Leu-Glu-Gly-Gln-Ala-Ala-ys-Glu-Phe-Ile-Ala-Trp-Leu-Val-X wherein X is selected from the group consisting of: (a) Lys, (b) ) Lys-Gly, (c) Lys-Gly-Arg; and (B) a peptide derivative; wherein the compound is substantially free of natural contaminants and has an insulinotropic activity that exceeds - the insulinotropic activity of GLP-I (1-36) or GLP-1 (1-37). The present invention also includes a compound that is selected from the group consisting of: (A) a peptide comprising the sequence: H-UA-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Stf- Tyr-Leu-Glu-Gly-GIn-Ala-Ala-Lys-Glu-Phe-lle-Ala-Tjp- eu-Val-X wherein X is selected from the group consisting of: (a) Lys, (b) Lys-Gly, (c) Lys-Gly-Arg; and (B) a peptide derivative; wherein the compound is substantially free of natural contaminants and has an insulinotropic activity at a concentration of at least 10"10 molar, Peptides of the following formula are of particular interest: (1) HzN-X-CO-R1 wherein R1 is an OH, OM, or -NR2R3 group, M is a pharmaceutically acceptable cation or a branched or unbranched lower alkyl group, Rz and R3 are the same or different and are selected from the group consisting of hydrogen and a branched lower alkyl group or not branched; X is a peptide comprising the sequence: Hista-Ala-Glu-Gly-Tlir-Phe-Tlir-Ser-As ^ GIn-Ia-Ala-Lys-Glu-P__e-p_-Ak-Tfp-Leu-Val-ys -G! Y-AiB NH2 is the amino group of the amino-terminal end of X; and CO is the carbonyl group of the carboxyl-terminal end of X; (2) the acid addition salts thereof; Y (3) the derivatives protected or partially protected thereof; wherein the compound has an insulinotropic activity that exceeds the insulinotropic activity of GLP-K1-36) or GLP-I (1-37). Another preferred group of molecules for use in the present invention consists of compounds claimed in US Pat. No. 5,512,549, which have the general formula: R'-Ala-Gtu-Gly 10- Thr-Phe-T_r-Scr-Asp, 5-Val-Ser-Ser-Tyr-cuM-Glu-Gly-Gln-AJa-AlaM-X_La-GIu-Phe-Ile-AÍaw - T? P- eu-Val-Lys-Gly35-Arg-R3 I Ra and pharmaceutically acceptable salts thereof, wherein R1 may be 4-imidazopropionyl, 4-imidazoacetyl or 4-imidazo-a, a-dimethylacetyl; R2 may be unbranched acyl of 6 to 10 carbon atoms, or - - be absent; R3 can be Gly-OH or NH2; and Xaa is Lys or Arg. The most preferred compounds for use in the present invention are those wherein Xaa is Arg and R 2 is an acyl of 6 to 10 unbranched carbon atoms. Highly preferred compounds for use in the present invention are those in which Xaa is Arg, R 2 is acyl of 6 to 10 unbranched carbon atoms and R 3 is Gly-OH. The most highly preferred compounds for use in the present invention are those in which Xaa is Arg, R 2 is an acyl of 6 to 10 unbranched carbon atoms, R 3 is Gly-OH and R 1 is g-imidazolepropionyl. . The most preferred compound for use in the present invention is that wherein Xaa is Arg, R 2 is unbranched acyl of 8 carbon atoms, R 3 is Gly-OH and R 1 is 4-imidazopropionyl. In the present invention, the use of a molecule claimed in US Pat. No. 5,120,712 is highly preferred. Such a molecule includes a peptide having the amino acid sequence: NHrHis -AIa-G? -Gly10- Thr-Phe-Thr-Ser-Asp, 3-Val-Ser-Ser-Tyr-Leu20- Ghi-Gly-Gln-Ala-AIa ^ -Lys-Glu-Phe-IIe- Ala * 0-T? P-Leu-V? D .Lys-G_y, 5-Arg-Gly3'-OH and a derivative of said peptide, wherein the peptide can be: a pharmaceutically acceptable acid addition salt of the peptide; a pharmaceutically acceptable carboxylate salt of the peptide; a pharmaceutically acceptable lower alkyl ester of the peptide; or a pharmaceutically acceptable amide of the peptide, wherein the amide may be an amide, lower alkylamide or lower dialkylamide. The use of GLP-I (7-36) amide or a pharmaceutically acceptable salt thereof in the present invention is highly preferred. The amino acid sequence of GLP-1 (7-36) amide is: NH2-His1-AIa-Glu-Gly, 0- Thr-Phe-Thr-Ser-Asp, s-V_I-Ser-Ser-Tyr-Leu20-Glu-Gly-Gln-Ala-Ala ^ -Lys-Glu-Phe -Ile-Ala30- Trp-Leu-Val-Lys-GI '-Arg-NHj The use of Val8-GLP-1 (7-37) OH or a pharmaceutically acceptable salt thereof in the present invention is very highly preferred. The amino acid sequence of Val8-GLP-1 (7-37) OH is: NH His7-Ala-G? -Gly, ° - Thr-Phe-Tbr-Ser-Asp ^ -Val-Ser-Ser-Tr-Leu20-Glu-Gly-Gto-Ala-AIa ^ -Lys-Glu-Pbe- IIe-Ala3 * - Trp-Leu-VaI-ys-Gly3-Ai ^ -Gly37-OH Preparation of the Compounds The methods for preparing the active compounds used in the present invention, mainly GLP-1, a GLP-1 analog or a GLP-1 derivative, or any related compound including an active fragment effective in reducing the mortality or morbidity after a fulminant attack when peripherally administered, are well known and described in U.S. Patent Nos. 5,118,666; 5,120,712 and 5,523,549. The amino acid portion of the active compound used in the present invention or a precursor thereof, is prepared in the following manner: 1) by synthetic chemistry in solid phase; 2) by means of a purification of GLP molecules from natural sources; 3) by recombinant DNA technology; or 4) by a combination of these methods. The chemical solid phase synthesis of polypeptides is well known in the art and can be found in general text of this field, such as - - Dugas and Penney (1981); Merrifield (1962); Stewart and Young (1969, 1984). For example, the amino acid portion can be synthesized by the solid phase methodology using a 430A peptide synthesizer (PE-Applied Biosystems, Inc., 850 Lincoln Center Drive, Foster City, CA 94404) and synthesis cycles supplied by PE- Applied Biosystems. BOC-amino acids and other reagents are commercially available from PE-Applied Biosystems and also from other chemical product distributors. The sequential BOC chemistry using double coupling protocols, are applied to the initial resins p-methyl benzhydrylamine for the production of. the C-terminal carboxamides. For the production of C-terminal acids, the corresponding PAM resin is used. Asn, Gln and Arg are coupled using previously formed hydroxybenzotriazole esters. The following side chain protective groups can be used: Arg, tosyl Asp, cyclohexyl Glu, cyclohexyl Ser, benzyl Thr, benzyl Tyr, 4-bromo-carbobenzoxy - - The deprotection of BOC can be carried out with trifluoroacetic acid in methylene chloride. After concluding the synthesis, the peptides can be deprotected and detached from the resin with anhydrous hydrogen fluoride (HF) containing 10% metacresol. The breaking of the protective groups of the side chain and the peptide of the resin is carried out at a temperature of -5 to 5 ° C, preferably in an ice bath for 60 minutes. After removal of the HF, the peptide / resin is washed with ether and the peptide is subjected to an extraction with glacial acetic acid and lyophilized. The techniques known to those skilled in the art can be employed. Recombinant DNA, to prepare the active compound used in the present invention. In fact, recombinant DNA methods may be preferable due to their high performance. The basic steps in recombinant production are: a) isolating a natural DNA sequence encoding a GLP-1 molecule of the present invention or constructing a synthetic or semi-synthetic DNA encoding the sequence of a GLP-1 molecule, b) placing the coding sequence in an expression vector, in a manner suitable for expressing the proteins either alone or in the form of fusion proteins, c) transforming an appropriate prokaryotic or eukaryotic host cell, with the expression vector, d) cultivate the transformed host cell under conditions that allow the expression of a GLP-i molecule, and e) recover and purify the GLP-1 molecule produced recombinantly. As stated above, the coding sequences may be completely synthetic or may be the result of modifications to the native glucagon coding DNA that is longer. A DNA sequence encoding preproglucagon is presented in Lund et al. (1982) and can be used as raw material in the production, by semisynthetic route, of the compounds of the present invention, by altering the native sequence to achieve the desired results. Synthetic genes can be constructed, whose transcription and translation in vi tro or in vivo results in the production of a GLP-1 molecule, by techniques known in the art. Due to the natural degeneracy of the genetic code, a person skilled in the art will recognize that a defined and determined number of DNA sequences can be constructed, all of which - - code for GLP-1 molecules of the present invention. The methodology of synthetic gene construction is known in the art (Brown et al., 1979). The DNA sequence is designed from the desired amino acid sequence using the genetic code, which is known to those skilled in the field of biology. Once designed, the sequence itself can be generated using a conventional DNA synthesis apparatus, such as the Model 380A or 380B DNA synthesizers (PE-Applied Biosystems, Inc., 850 Lincoln Center Drive, Foster City, CA 94404). To express the amino acid portion of a compound used in the present invention, a synthetic DNA sequence is inserted into any of a number of appropriate recombinant DNA expression vectors, by the use of appropriate restriction endonucleases.

(Maniatis et al., 1989). The cleavage sites by restriction endonucleases are engineered to be at either end of the DNA encoding the GLP-1 molecule to facilitate its isolation and for its integration, amplification and expression in vectors known in the art. Particularly employed endonucleases will be dictated by the restriction endonuclease disruption pattern of the parent expression vector employed. The restriction sites are selected to appropriately orient the coding sequence with control sequences, thereby achieving an appropriate frame reading and adequate expression of the protein of interest. The coding sequence must be positioned in the appropriate reading frame with the promoter and the ribosome binding site of the expression vector, both of which are functional in the host cell in which the protein is to be expressed. To achieve efficient transcription of the synthetic gene, it must be operably associated with a promoter-operator region. Therefore, the promoter-operator region of the synthetic gene is placed in the same sequential orientation with respect to the ATG start codon of the synthetic gene. A variety of expression vectors useful for the transformation of prokaryotic and eukaryotic cells are known (Promega Catalog, 1992, Stratagene Catalog, 1992). Likewise, US Pat. No. 4,710,473 discloses circular DNA plasmid transformation vectors useful for the expression of exogenous genes in E. coli at high concentrations. These plasmids are useful as transformation vectors in recombinant DNA procedures and (a) confer on the plasmid the ability of autonomous replication in a host cell; (b) confer an autonomous plasmid replication in relation to the temperature at which the cultures of the host cell are maintained; (c) stabilize the conservation of the plasmid in the populations of the host cells; (d) direct synthesis of a protein product, indicative of the conservation of the plasmid in a population of host cells; (e) providing serial restriction endonuclease recognition sites, unique to the plasmid; and (f) terminate mRNA transcription. These circular DNA plasmids are useful as vectors in recombinant DNA procedures to ensure high levels of expression of exogenous genes. Having constructed an expression vector for the amino acid portion of a compound used in the present invention, the next step is to place the vector in a suitable cell and thereby construct a recombinant host cell useful for expression of the polypeptide. The techniques for transforming cells with recombinant DNA vectors are known and can be found in general references such as Maniatis, et al. , supra. Host cells can be constructed from - eukaryotic or prokaryotic cells. Prokaryotic host cells usually produce the protein in larger amounts and are easier to grow. Proteins expressed at high levels in bacterial expression systems characteristically aggregate in the form of granules or inclusion bodies, which contain high amounts of the overexpressed protein. Such protein aggregates should typically be recovered, solubilized, denatured and reconstituted, using techniques known in the art (Kreuger et al., 1990; US Pat. No. 4,923,967). Preparation of GLP-1 Analogs and Derivatives Alterations can be made to a GLP-1 precursor or to an amino acid sequence of GLP-1 to produce a GLP-1 analog or a GLP-1 derivative or a fragment of the same, by known methods: chemical modification, enzymatic modification or a combination of chemical and enzymatic modifications. Classical phase solution techniques and semi-synthetic methods can also be used to prepare the GLP-1 molecules used in the present invention. The methods for preparing the GLP-1 molecules of the present invention are known to those skilled in the peptide chemistry.

- - In addition, the addition of an acyl group to the epsilon-amino group of Lys34 can be carried out using any of a variety of methods known in the art (Bioconjugate Chem. 1990, Hashimoto et al., 1989). For example, an N-hydroxysuccinimide ester of octanoic acid can be added to the lysyl-epsilon amino group using 50% acetonitrile in borate buffer. The peptide can be acylated before or after the imidazole group is added. In addition, if the peptide is prepared recombinantly, acylation is possible before enzymatic cleavage. Likewise, the lysine in the GLP-1 derivative can be acylated in the manner taught in International Publication WO 96/29342. The existence and preparation of a multitude of protected, unprotected and partially protected, natural and non-natural analogs, and derivatives of GLP-1 (7-36) amide and GLP-I (7-37) molecules, have been described in the scientific literature (U.S. Patent Nos. 5,120,712, 5,545,618 and 5,118,666, Orskot et al., 1989, WO 91/11457). Optionally, the amino-terminal and carboxyl-terminal residues of GLP-1 derivatives can be protected or optionally only one of the terminal ends is protected. Reactions for the formation and removal of such protecting groups are described in work known to those skilled in the art, including, for example, Protective Groups in Organic Chemistry 1973, Green, 1981 and Schroder and Lübke, 1965. Some representatives of amino groups Protectants include, for example, formyl, acetyl, isopropyl, butoxycarbonyl, fluorenylmethoxycarbonyl, carbobenzyloxy groups and the like. Some representative groups of carboxyl-protecting groups include, for example, benzyl ester, methyl ester, ethyl ester, t-butyl ester, p-nitrophenyl ester and the like. The carboxyl-terminal derivatives, lower alkyl ester, GLP-1 used in the present invention, are prepared by reacting the desired alkanol (of 1 to 4 carbon atoms) with the desired polypeptide, in the presence of a catalytic acid such as hydrochloric acid. Suitable conditions for such alkyl ester formations include a reaction temperature of about 50 ° C and a reaction time of about 1 to about 3 hours. Similarly, the alkyl ester derivatives of the Asp and / or Glu residues can also be formed. The preparation of a carboxamide derivative of a compound used in the present invention is obtained, for example, in the manner described in Stewart et al. (1984) . A pharmaceutically acceptable salt of GLP-1 or a GLP-1 analogue or a GLP-1 derivative can also be used in the present invention. Acids commonly used to form acid addition salts are inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric and the like, and organic acids such as p-toluenesulfonic, methanesulfonic, oxalic, p-bromophenylsulphonic, carbonic, succinic acid , citric, benzoic, acetic and the like. Examples of such salts include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, acid phosphate, diacid phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate , heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butin-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate , xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propansulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid. Basic addition salts include those derived from inorganic bases, such as ammonium hydroxides or alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates and the like. Such bases useful in the preparation of the salts of the present invention, include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate and the like. Salt forms are particularly preferred. GLP-1, GLP-1 analog or GLP-1 derivative used in the present invention, can be formulated with one or more excipients before being used in the present invention. For example, the active compound used in the present invention can be complexed with a divalent metal cation, by known methods. Such metal cations include, for example, Zn ++, Mn ++, Fe ++, Co ++, Cd ++, Ni ++ and the like. Compositions of the Present Invention Optionally, the active compound used in the present invention can be combined with a pharmaceutically acceptable buffer and the pH can be adjusted to provide acceptable stability and an acceptable pH for parenteral administration. Optionally, one or more pharmaceutically acceptable antimicrobial agents can be added. Metacresol and phenol are preferred as pharmaceutically acceptable antimicrobial agents. One or more pharmaceutically acceptable salts can be added to adjust the ionic strength or tonicity. One or more excipients may be added to further adjust the isotonicity of the formulation. Glycerin is an example of an excipient to adjust isotonicity. The GLP-1 receptors and the signal transduction cascade initiated by the binding of the ligand to the GLP-1 receptor are described in International Publication WO 96/25487; Thorens et al. , 1993; and Widmann et al. , 1994. The GLP-1 receptor is a membrane protein with seven transmembrane domains, coupled to the heterotrimeric G proteins that link receptor activation upon binding of the ligand, to the production of intracellular secondary messages, especially cyclic adenosine monophosphate ( cAMP). CAMP, in turn, activates a specific protein kinase, called cAMP-dependent protein kinase (protein kinase A, PKA). This enzyme phosphorylates a number of key response elements present in the promoter region of certain genes. In pancreatic ß cells and other neuroendocrine cells, the phosphorylation of some specific proteins of the regulated secretory pathway stimulates the secretion of peptides by stimulating the exocytosis of secretory granules. Several compounds are known that stimulate the secretion of endogenous GLP-1. For example, exposure of STC-1 cells to certain secretagogues, such as the adenylate cyclase activator, forskolin, or the protein kinase C stimulating agent, 12-0-tetradecanoylfobol-13-acetate (TPA), causes an increase in significant in the release of GLP-1 (Abella et al., 1994). The STC-1 cell line originates from an intestinal tumor in transgenic mice carrying insulin-promoting oncogenes and it is known that STC-1 cells contain transcripts of proglucagon mRNA, from which GLP-1 is generated. Other compounds, such as somatostatin, gastric inhibitory polypeptide, glucose-dependent insulinotropic peptide, bombesin, peptide related to the calcitonin gene, gastrin-releasing peptide, cholinergic agonists, the β-adrenergic agonist isoproterenol and the muscarinic cholinergic agonist betanechol, similarly, they also cause the release of endogenous GLP-1 (Plarsancie et al., 1994, Orskov et al., 1986, Brubaker, 1991, Bucho, et al., 1987). Administration of Compositions Administration can be by any route that the physician knows to be effective, except that parenteral administration directly in the central nervous system is not a route taught or claimed in this invention. Peripheral-parenteral administration is preferred. Parenteral administration is commonly understood in the medical literature as the injection of a pharmaceutical form into the body, by a sterile syringe or some other mechanical device such as an infusion pump. For the purposes of the present invention, peripheral parenteral routes include the intravenous, intramuscular, subcutaneous and intraperitoneal routes of administration. The intravenous, intramuscular and subcutaneous routes of administration of the compounds used in the present invention are most preferred. The intravenous and subcutaneous routes of administration of the compounds used in the present invention are still more highly preferred. For parenteral administration, an active compound used in the present invention is preferably combined with distilled water, at an appropriate pH. Certain compounds used in the present invention to effect the reduction of mortality and morbidity, may also be capable of being administered orally, rectally, nasally or other respiratory routes, which are not parenteral routes. Of the non-parenteral routes, the low respiratory route is preferred for the administration of the peptides used in the present invention. Various formulations of peptide compounds for administration in the lower respiratory tract are described in U.S. Patent Nos. 5,284,656 and 5,364,838. International Publication WO 96/19197 describes aerosol formulations of various peptides suitable for increasing the absorption in the lower respiratory tract of the compounds used in the present invention. The oral administration route is preferred for the compounds used in the present invention. Additional pharmaceutical methods can be used to control the duration of the action. Controlled release preparations can be prepared by using polymers to complex or absorb the active compound used in the present invention. Extended duration can be obtained by selecting appropriate macromolecules, for example polyesters, polyamino acids, polyvinylpyrrolidone, ethylene vinyl acetate, methylcellulose, carboxymethylcellulose or protamine sulfate, and selecting the concentration of the macromolecules, as well as the incorporation methods, in order to prolong the release of the drug. Another possible method for extending the duration of the action by controlled release preparations is to incorporate an active compound used in the present invention into particles of a polymeric material such as polyesters, polyamino acids, hydrogels, poly (lactic acid) or ethylene copolymers and vinyl acetate. Alternatively, instead of incorporating a compound in these polymer particles, it is possible to trap a compound of the present invention in microcapsules prepared, for example, by co-preservation techniques or by interfacial polymerization, for example, hydroxymethylcellulose microcapsules or gelatin microcapsules, respectively , or in colloidal drug delivery systems, for example liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules, or in macroemulsions. These techniques are known to those skilled in the art and are described, eg, in Remington Pharmaceutical Sciences, 1980. Dosage The dose of GLP-1, GLP-1 analog or GLP-1 derivatives or active fragments effective in a subject Particular to reduce mortality and morbidity caused by a fulminant attack, will depend on a number of factors, which include the sex of the subject, weight and age, the severity of the attack, the subtype of attack, the route of administration and the bioavailability, the persistence of the compound administered in the body, the formulation and the potency. When administration is intermittent, the dose per administration should also take into account the interval between the doses and the bioavailability of the compound administered. When administration is continuous, a suitable dose range is between 0.25 and 6 pmol / kg / min, preferably between 0.5 to approximately 1.2 pmol / kg / min. It is within the knowledge of an ordinary doctor, title the dose and time of administration of the compositions containing GLP-1, GLP-1 analogs or GLP-1 derivatives or fragments thereof, to achieve the desired clinical result, the reduction of mortality and morbidity after a fulminant attack by the control of glucose. In one embodiment, the reduction in plasma glucose concentration below about 7 mmol / L is a goal after a fulminating attack. The term "pharmaceutically acceptable" as used herein, means suitable to be administered to a human being; that is, it does not contain toxic elements, undesirable contaminants or the like and does not interfere with the activity of the active compounds in the formulation. Numerous GLP-1 analogs and derivatives having an isoelectric point in the range of 4.8 to 7.5 have been described, and include for example: GLP-1 (7-36) NH2 Gly8-GLP-1 (7-36) NH2 Gln9 -GLP-l (7-37) Fulminant Attack Diagnosis A diagnosis of "fulminating attack" is one that involves medical judgment. The treatment that is the object of the present invention is generally administered to a person during the acute phase of the fulminating attack. A patient in need of the compounds used in the present invention is someone who is in the acute phase of a fulminant attack and who is unable to self-regulate blood glucose. A patient is unable to perform self-regulation if that patient: (1) was previously diagnosed with insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM), in accordance with the definitions of the National Diabetes Data Group (Diabetes, 1979); (2) that has a blood glucose level greater than 11 mmol / l, even without a prior diagnosis of diabetes; or (3) having an abnormal tolerance to glucose. The dose of GLP-1, GLP-1 analog or GLP-1 derivative effective to normalize a patient's blood glucose level, will depend on a number of factors, including, but not limited to, the sex of the patient. patient, age and weight, the severity of the inability to regulate blood glucose, the underlying causes of the inability to regulate blood glucose, if glucose or some other source of carbohydrate is administered simultaneously, the route of administration and the bioavailability, persistence in the body, formulation and potency. When administration is continuous, a suitable dose range is between 0.25 and 6 pmol / kg body weight / min, preferably from about 0.5 to about 1.2 pmol / kg / minute. When administration is intermittent, the dose per administration should take into account the interval between the doses, the bioavailability of GLP-1, GLP-1 analog or GLP-1 derivative and the concentration necessary to have the effect of normalizing glucose blood It is within the knowledge of an ordinary doctor, titrate the dose and the frequency of administration of GLP-1 and GLP-1 analogue or GLP-1 derivative, to achieve the desired clinical result. EXAMPLES The present invention will be more readily understood with reference to specific examples, which are provided to illustrate embodiments of the present invention.

- Example 1: Effects of Subcutaneous Infusion of GLP-1 (7-30) on Blood Glucose in Persons with NIDDM GLP-I (7-36) amide was administered by subcutaneous infusion at a dose of 1.2 pmol / kg / hr during 10 hours at night, to 5 patients suffering from non-insulin-dependent diabetes mellitus (NIDDM). As a control, insulin was administered as a continuous infusion in the same 5 patients, but on a different day from the infusion of GLP-I (7-36) amide. Insulin infusion rate was adjusted every 2 hours to achieve optimal control and avoid hypoglycemia. As demonstrated in the data of Table 1 and Figure 1, subcutaneous infusion of GLP-1 (7-36) amide almost completely normalized blood glucose without inducing hypoglycaemia in any of the patients. The metabolic control with GLP-1 (7-36) amide was better than that achieved with insulin and the average blood glucose concentration was lower for the treatment with GLP-1 (7-36) amide than for the control, in an amount statistically significant at 23:00, 0:00 and 1:00.

Table 1: Average blood glucose concentration in 5 patients with NIDDM, administered by continuous infusion for 10 hours at night with GLP-K7-36) amide. In a control study with the same patients, on a different day, insulin was administered by continuous infusion.

Example 2: Effects of Subcutaneous Infusion of GLP-1 (7-36) During Meals on Blood Glucose Concentration in People with NIDDM During the day, GLP-1 (7-36) amide was administered by infusion to 5 patients with DMNID for 3 hours during breakfast, lunch and dinner. The infusion times were from 7: 30-10: 30 (breakfast), 10: 30-1: 30 (lunch) and 4: 30-7: 30 (dinner), as indicated in the Figure 2. In a control experiment, in the same 5 patients with NIDDM, performed on a different day, insulin was injected subcutaneously just before starting meals, as indicated in Figure 2. While the GLP- 1 was administered by infusion, postprandial glucose excursions observed with insulin injection were eliminated and normal blood glucose levels were maintained. Immediately after finishing each infusion with GLP-I (7-36) amide, the blood glucose concentration increased significantly. No undesirable side effects were observed at GLP-I (7-36) amide. These data indicate that the infusion with GLP-l (7-36) amide more effectively controls the postprandial glucose levels than the insulin injection and that the control is effective as long as the infusion of GLP-K7-36 is continued. ) amide.

Table 2: Average blood glucose concentration in 5 patients with NIDDM who were administered by infusion of GLP-I (7-36) amide for 3 hours, starting at the beginning of each meal. In a control study with the same patients, on a different day, insulin was administered by subcutaneous injection just before each meal. Meals started at 7:30, 10:30 and 16:30. hours .

DOCUMENTS CITED Abello, Jr. et al., Endocrinol. 134: 2011-2017a (1994). Araki, N., et al., Journal of Cerebral Blood Flow and Metabolis 12: 469-476 (1992). Barbash, B.I., et al., J. Am. Coll. Cardiol. 22: 707-713 (1993). Bioconjugate Chem. "Chemical Modifications of Proteins: History and Applications ", pp. 1-212 (1990) Broderick, J.P., et al., Stroke 26: 484-487 (1995) Brown, et al., (1979) Methods in Enzymology, Academic Press, N.Y., Vol. 69, pp. 109-151. Brubaker, P.L., Endocrinol. 128: 3175-03182 (1991). Buchan, A.M.J., et al., Gastroenterol. 93: 791-800 (1987).

Cazzato, G., et al., Italina Journal of Neurological Sciences 12: 283-288 (1991). de Courier-Myers, G., et al., Stroke 19: 623-630 (1988). deFalco, F.A., et al., Schweizer Archiv Für Neurologie und Psychatrie 144: 233-239 (1993). National Diabetes Data Group, Diabetes 28: 1039-1057 (1979). Dietrich, W.D., et al., Stroke 24: 111-116 (1993). Duckrow, R.B., et al., Annals of Neurology 17: 262-272 (1985). Duckrow, R.B., et al., Stroke 18: 52-58 (1987). Dugas, H. and Penney, C, Bioorganic Chemistry, Springer-Verlag, New York (1981), pp. 54-92.

- - Fuller, J.H., Diabet. Metab. 19: 96-99 (1993). Granger, C.B., et al., J. Am. Coll. Cardiol. 21 (4): 920,925 (1993). Gray, C.S., et al., Diabetic Medicine 4: 237-240 (1987). Green, T.H., Protective Groups in Organic Synthesis, Wiley, New York (1981). Grines, C, et ai., N. Engl. J. Med. 328: 673-679 (1993).

Gutniak, M., et al., Diabetes Care 17: 1039-1044 (1994). Gutniak, M., et al., New England J. of Medicine 326 (20): 1316-1322 (1992). Hamsten, A., et al., J. Int. Med. 736: 1-3 (1994) 236 Suppl.

Hashimoto et al., Pharmaceutical Res. 6 (2): 171-176 (1989).

Hendra, T.J., et al., Diabetes Res. Clin. Pract 16: 213-220 (1992). Karlson, B.W., et al., Diabet. Med. 10 (5): 449-454 (1993).

Kiers, L., et al., Journal of Neurology, Neurosurgery, Psychiatry 55: 263-270 (1992). Krcymann, B., et al., Lancet 2: 1300-1303 (1987). Kreuger, et al. (1990) in Protein Folding, Gierasch and King, eds. pp. 136-142. American Association for the Advancement of Science Publication? 89-18S, Washington, D.C. Lehto, S., et al., Stroke 27: 63-8 (1966). Levine, S.R., Annais of Neurology 23: 416-418 (1988). Lund, et al., Proc. Nati Acad. Sci. USA 79: 345-349 (1982).

Malmberg, K. and Rydén, L., Eur. Heart J. 9: 256-264 (1988).

Malmberg, K., et al., J. Am. Coll ege Cardiology 26: 57-65 (1995). Malmberg, K.A., et al. , Diabetes Care 17: 1007-1014 (1994). Maniatis et al. , Molecular Cloning: A Laboratory Manual, Cold Springs Harbor Laboratory Press, N.Y., Vol. 1-3 (1989). Mentlein, R., et al., Eur. J. Biochem. 214: 829-835 (1993).

Merrifield, J.M., Chem. Soc. 85: 2149 (1962). Mojsov, S., Int. J. Peptide Protein Research 40: 333-343 (1992). Moulin, T., et al., European Neurology 38: 10-27 (1997).

Nauck, M.A., et ai., Diabetologia 36: 741-744. Nauck, M.A., et al. , J. Clin. Invest. 91: 301-307 (1993). O'Neill, P.A., et al. , Stroke 22: 842-847 (1992). Orskov, C, et al. , Endocrinol. 119: 1467-1475 (1986). Orskov, C, et al. , J. Biol. Chem. 264 (22): 12826-12829 (1989). Plaisancie, P., et al. , Endocrinol. 135: 2348-2403 (1994). Protective Groups in Organic Chemistry, Plenum Press, London and New York (1973). Remington's Pharmaceutical Sciences (1980). Schroder and Lübke, The Peptides, Vol. 1, Academic Press, London and New York (1965). Silvka, A.P., Brain Research 562: 66-70 (1991).

Stewart and Young, Solid Phase Peptide Synthesis, Freeman, San Francisco (1969), pp. 24-66. Stewart, J.M., et al. , Solid Phase Peptide Synthesis, Pierce Chemical Company Press (1984). Stone, P., et al. , J. Am. Coll. Cardiol. 14: 49-57 (1989).

The Promega Biological Research Products Ca tal ogue (1992) (Promega Corp., 2800 Woods Hollow Road, Madison, Wl 53711-5399). The Stratagene Cloning Systems Catalog (1992) (Stratagene Corp., 11011 North Torrey Pines Road, La Jolla, CA 92037).

Thorens, B., et al., Diabetes 42: 1219-1225 (1993). Tuomilehto, J., et al. , Stroke 27: 210-215 (1996). Wagner, K.R., et al., Journal of Cerebral Blood Flow. and Metabolism 12: 213-22 (1992). Wass, C.T., and Lanier, W.L., Mayo Clini c Proceedings 71: 801-812 (1996). Weir, C.J., et al. , BMJ 31 (7090): 1303-6 (1997). Widmann, C, et al. , Mol. Pharmacol. 45: 1029-1035 (1994).

U.S. Patent Nos. 4,710,473; 4,923,967; 5,118,666; 5,188,666; 5,120,712; 5,284,656; 5,364,838; ,545,618; 5,512,549; 5,523,549. Foreign Patent Nos. WO 91/11457; WO 96/29342; WO 96/25487; WO 96/19197. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Sequence Listing < 110 > Eli Lilly and Company < 120 > USE OF GLP-1 OR ANALOGS IN THE TREATMENT OF FULMINING CRISIS < 130 > X-11158 < 140 > PCT / US99 / 22026 < 141 > 1999-09-22 < 150 > US 60/101719 < 151 > 1998-09-24 < 160 > 35 < 170 > Patentln Ver. 3.0 < 210 > 1 < 211 > 31 < 212 > PRT < 213 > Homo sapiens < 400 > 1 His Wing Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Wing Lys Glu Phe lie Wing Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 2 < 211 > 28 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 400 > 2 - 2 - His Wing Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Wing Lys Glu Phe He Wing Trp Leu Val Lys 20 25 < 210 > 3 < 211 > 29 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 400 > 3 His Wing Glu Gly Thr Phe Thr Being Asp Val Being Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly 20 25 < 210 > 4 < 211 > 30 < 212 > PRT < 213 > Homo sapiens < 400 > 4 His Wing Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Wing Lys Glu Phe He Wing Trp Leu Val Lys Gly Arg 20 25 30 < 210 > 5 < 211 > 31 < 212 > PRT < 213 > Artificial - 3 - < 223 > Synthetic construction < 400 > 5 His Val Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Wing Lys Glu Phe He Wing Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 6 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 400 > 6 His Wing Gln Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 7 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > (3) .. (3) < 223 > Xaa in position 3 is D-Gln < 400 > 7 - 4 - His Wing Xaa Gly Thr Phe Thr Being Asp Val Being Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe He Wing Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 8 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 400 > 8 His Wing Glu Gly Thr Phe Thr Ser Asp Thr Ser Lys Tyr Leu Glu Gly 1 5 10 15 Gln Ala Wing Lys Glu Phe He Wing Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 9 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 400 > 9 His Wing Glu Gly Thr Phe Thr Ser Asp Val Ser Lys Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 10 < 211 > 28 < 212 > PRT < 213 > Artificial - 5 - < 223 > Synthetic construction < 221 > VARIANT < 222 > ( twenty ) . . (20) < 223 > Xaa in position 20 is D-Lys, Gly, Ser, Ala, Leu, Lie, Gln, Arg, D-Arg and Met < 221 > VARIANT < 222 > (28) . (28) < 223 > Xaa at position 28 is D-Lys, Gly, Ser, Ala, Leu, Lie, Gln, Arg, D-Arg and Met < 400 > 10 His Wing Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Wing Ala Xaa Glu Phe He Wing Trp Leu Val Xaa 20 25 < 210 > 11 < 211 > 29 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > (twenty ) . . (20) < 223 > Xaa at position 20 is D-Lys, Gly, Ser, Ala, Leu, Lie, Gln, Arg, D-Arg and Met < 221 > VARIANT < 222 > (28) .. (28) < 223 > Xaa in position 28 is D-Lys, Gly, Ser, Ala, Leu, - 6 - lie, Gln, Arg, D-Arg and Met < 400 > 11 His Wing Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Xaa Glu Phe He Wing Trp Leu Val Xaa Gly 20 25 < 210 > 12 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > ( twenty ) . . (20) < 223 > Xaa at position 20 is D-Lys, Gly, Ser, Ala, Leu, Lie, Gln, Arg, D-Arg and Met < 221 > VARIANT < 222 > (28) .. (28) < 223 > Xaa at position 28 is D-Lys, Gly, Ser, Ala, Leu, Lie, Gln, Arg, D-Arg and Met < 221 > VARIANT < 222 > (30) .. (30) < 223 > Xaa at position 30 is D-Lys, Gly, Ser, Ala, Leu, Lie, Gln, Met and D-Arg < 400 > 12 - 7 - His Wing Glu Gly Thr Phe Thr Being Asp Val Being Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Xaa Glu Phe He Ala Trp Leu Val Xaa Gly Xaa Gly 20 25 30 < 210 > 13 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > (10) .. (10) < 223 > Xaa in position 10 is Tyr or Val < 221 > VARIANT < 222 > (12) .. (12) < 223 > Xaa in position 12 is Lys or Ser < 221 > VARIANT < 222 > (15) .. (15) < 223 > Xaa at position 15 is Asp or Glu < 221 > VARIANT < 222 > (16) .. (16) < 223 > Xaa in position 16 is Ser or Gly < 221 > VARIANT < 222 > (17) .. (17) < 223 > Xaa at position 17 is Arg or Gln < 221 > VARIANT < 222 > (18) .. (18) < 223 > Xaa at position 18 is Arg or Ala < 221 > VARIANT < 222 > (20) .. (20) < 223 > Xaa at position 20 is Gln or Lys < 400 > 13 His Wing Glu Gly Thr Phe Thr Ser Asp Xaa Ser Xaa Tyr Leu Xaa Xaa 1 5 10 15 Xaa Xaa Ala Xaa Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 14 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 400 > 14 Tyr Ala Gl? Gly Thr Phe Thr Being Asp Val Being Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Wing Lys Glu Phe He Wing Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 15 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > ( 1 ) . . (1) - 9 - < 223 > Xaa at position 1 is N-acetyl-His < 400 > fifteen Xaa Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 16 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > (1) .. (1) < 223 > Xaa at position 1 is N-isopropyl-His < 400 > 16 Xaa Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 17 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > (2 ) . . (2) < 223 > Xaa in position 2 is D-Ala - 10 - < 400 > 17 His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 18 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > ( 3 ) . . (3) < 223 > Xaa in position 3 is D-Glu < 400 > 18 His Wing Xaa Gly Thr Phe Thr Being Asp Val Being Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 19 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 400 > 19 - 11 - His Wing Asp Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Wing Lys Glu Phe He Wing Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 20 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > ( 3 ) . . (3) < 223 > Xaa in position 3 is D-Asp < 400 > 20 His Ala Xaa Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10. fifteen Gln Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 21 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > ( 4 ) . . (4) < 223 > Xaa in position 4 is D-Phe < 400 > 21 12 - His Wing Glu Xaa Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Wing Lys Glu Phe He Wing Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 22 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 400 > 22 His Wing Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Ser 1 5 10 15 Arg Arg Ala Gln Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 23 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 400 > 2. 3 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 24 < 211 > 31 < 212 > PRT < 213 > Artificial - 13 - < 223 > Synthetic construction < 221 > VARIANT < 222 > (1) .. (1) < 223 > Xaa at position 1 is His, D-histidine, deamino-histidine, 2-aminohistidine, beta-hydroxyhistidine, homohistidine, alpha-fluoromethylhistidine and allymethylhistidine < 221 > VARIANT < 222 > (2) .. (2) < 223 > Xaa in position 2 is Ala, Gly, Val, Thr, lie and alpha-ethyl-Ala < 221 > VARIANT < 222 > (15) .. (15) < 223 > Xaa at position 15 is Glu, Gln, Ala, Thr, Ser and Gly < 221 > VARIANT < 222 > (21) .. (21) < 223 > Xaa in position 21 is Glu, Gln, Ala, Thr, Ser and Gly < 221 > VARIANT < 222 > (31) .. (31) < 223 > Xaa at position 31 is Glu-OH or is absent < 400 > 24 14 - Xaa Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Xaa Gly 1 5 10 15 Gln Ala Ala Lys Xaa Phe He Wing Trp Leu Val Lys Gly Arg Xaa 20 25 30 < 210 > 25 < 211 > 30 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 400 > 25 His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe He Wing Trp Leu Val Lys Gly Arg 20 25 30 < 210 > 26 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > ( 3 ) . . (3) < 223 > Xaa in position 3 is acetyl-Lys < 400 > 26 His Wing Xaa Gly Thr Phe Thr Being Asp Val Being Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 27 - 15 - < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 400 > 27 His Wing Thr Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Wing Wing Lys Glu Phe He Wing Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 28 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > ( 3 ) . . (3) < 223 > Xaa in position 3 is D-Thr < 400 > 28 His Wing Xaa Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Wing Wing Lys Glu Phe He Wing Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 29 < 211 > 31 < 212 > PRT < 213 > Artificial - 16 - < 223 > Synthetic construction < 400 > 29 His Wing Asn Gly Thr Phe Thr Being Asp Val Being Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 30 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > (3) .. (3) < 223 > Xaa in position 3 is D-Asn < 400 > 30 His Wing Xaa Gly Thr Phe Thr Being Asp Val Being Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 31 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 400 > 31 - 17 - His Wing Glu Gly Thr Phe Thr Being Asp Val Being Ser Tyr Leu Glu Gly 1 5 10 15 Arg Wing Wing Lys Glu Phe He Wing Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 32 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 400 > 32 His Ala Gl? Gly Thr Phe Thr Being Asp Val Being Ser Tyr Leu Glu Gly 1 5 10 15 Gln Arg Ala Lys Glu Phe He Wing Trp Leu Val Lys Gly Arg Gly 20 25 30 < 210 > 33 < 211 > 28 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > (28) . (28) < 223 > Xaa at position 28 is Lys and Lys-Gly < 400 > 33 His Wing Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Wing Lys Glu Phe He Wing Trp Leu Val Xaa 20 25 < 210 > 34 - 18 - < 211 > 28 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > (28) .. (28) < 223 > Xaa at position 28 is Lys, Lys-Gly, Lys-Gly-Arg < 400 > 3. 4 His Wing Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Wing Lys Glu Phe He Wing Trp Leu Val Xaa 20 25 < 210 > 35 < 211 > 31 < 212 > PRT < 213 > Artificial < 223 > Synthetic construction < 221 > VARIANT < 222 > ( 1 ) . . (1) < 223 > Xaa at position 1 is 4-imidazopropionyl, 4-imidazoacetyl, 4-imidazo-alpha or alpha-dimethylacetyl < 221 > VARIANT < 222 > (20) .. (20) < 223 > Xaa in position 20 is Lys or Arg < 221 > VARIANT < 222 > (31) .. (31) - 19 - < 223 > Xaa at position 31 is Gly or is absent < 400 > 35 Xaa Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Xaa Glu Phe He Ala Trp Leu Val Lys Gly Arg Xaa 20 25 30

Claims (15)

1. -
2. CLAIMS Having described the invention as background, the content of the following claims is claimed as property: 1. The use of a compound selected from the group consisting of GLP-1, GLP-1 analogs, GLP-1 derivatives and pharmaceutically salts acceptable for the same, for the preparation of a drug to reduce mortality and morbidity after a fulminant attack, at an effective dose to normalize glucose the blood glucose concentration. 2. The use according to claim 1, characterized in that the compound is administered intravenously.
3. 3. Use in accordance with the claim 1, characterized in that the compound is administered subcutaneously.
4. 4. Use in accordance with the claim 2, characterized in that the administration is continuous.
5. 5. Use in accordance with the claim 4, characterized in that the rate of administration of the compound is between 0.25 and 6 pmol / kg / min.
6. 6. Use in accordance with the claim 5, characterized in that the rate of administration of the compound is between 0.5 and 2.4 pmol / kg / min. - -
7. 7. The use according to claim 5, characterized in that the rate of administration of the compound is between about 0.5 and about 1.2 pmol / kg / min.
8. 8. Use in accordance with the claim 2, characterized in that the compound is administered intermittently.
9. 9. The use according to claim 2, characterized in that the compound is administered intravenously and is also administered by some other parenteral route.
10. 10. The use according to claim 9, characterized in that the other parenteral route is the subcutaneous route.
11. 11. Use in accordance with the claim 1, characterized in that the compound is GLP-I (7-36) amide, or a pharmaceutically acceptable salt thereof.
12. 12. The use according to claim 1, characterized in that the compound is GLP-1 (7 to 37, or a pharmaceutically acceptable salt thereof. The use according to claim 1, characterized in that the compound is Val8- GLP-1 (7-37), or a pharmaceutically salt thereof 14. The use of a compound that exerts an insulinotropic activity by interacting with the same receptor or receptors, with which GLP-1, GLP-analogs 1 and GLP-1 derivatives interact to exert their insulinotropic activity, for the preparation of a drug to reduce morbidity and mortality after a fulminant attack 15. The use of a compound that increases the sensitivity of insulin to interact with the same receptor or receptors with which GLP-1, GLP-1 analogs and GLP-1 derivatives interact to increase sensitivity, for the preparation of a drug to reduce morbidity and mortality after an attack ulminating