2003 role of incretins in glucose homeostasis and diabetes


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Dr. Mdasir Bashir
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  • Degradation of GLP-1 GLP-1 is a 30 amino acid peptide. This peptide is rapidly degraded by the enzyme DPP-4, present in human serum and universally expressed on endothelial cells. DPP-4 hydrolyses the peptide between alanine in position 2 and the remainder of the amino acid chain. After cleavage, the resulting peptide fragment does not exhibit incretin activity [Gallwitz et al, 1994; Mentlein et al, 1993]. GLP-1 exerts its insulinotropic effects by binding to receptors on β-cells. One approach to improving GLP-1 activity is through the administration of incretin mimetics. These compounds are molecular analogues of GLP-1 which have the ability to activate β-cell receptors but which are structurally different enough to reduce or prevent degradation by DPP-4. A second approach involves the use of incretin enhancers; these prolong the bioactivity of GLP-1 by inhibiting the action of DPP-4 [Drucker 2006; Drucker 2001]. REFERENCES Drucker DJ. Cell Metab . 2006;3:153-165. Drucker DJ. Curr Pharm Des . 2001;7:1399-1412. Gallwitz B, Witt M, Paetzold G, et al. Eur J Biochem . 1994;225:1151-1156. Mentlein R, Gallwitz B, Schmidt WE. Eur J Biochem . 1993;214:829-835.
  • Postprandial GLP-1 levels are decreased in people with IGT and Type 2 diabetes This slide illustrates plasma GLP-1 response to meal ingestion in age- and weight-matched individuals with normal glucose tolerance (NGT) compared with individuals with impaired glucose tolerance (IGT) and Type 2 diabetes (n=102). The meal test began 3 days after discontinuation of oral glucose-lowering medication and following an overnight fast. Blood was sampled before the start of the meal and over 4 hours post-meal. Plasma GLP-1 levels rose shortly after meal ingestion in all groups. GLP-1 concentrations were significantly lower in the Type 2 diabetes group compared with the NGT group beginning at 60 minutes and continuing for an additional 90 minutes ( P <0.05). A similar trend was apparent for IGT compared with NGT. These results demonstrate that the meal-stimulated GLP-1 response is depressed in individuals with both Type 2 diabetes and IGT compared with their NGT counterparts. REFERENCE Toft-Nielsen M, Damholt M, Madsbad S, et al. J Clin Endocrinol Metab . 2001;86:3717-3723.
  • GLP-1 enhancement Postprandial plasma levels of GLP-1 are depressed in Type 2 diabetes, indicating an impaired GLP-1 response to nutrient ingestion. For this reason, continuous GLP-1 infusion therapy has proven useful in short-term studies but is not a practical long-term therapy. The effort to identify effective forms of GLP-1 administration is challenged by its extremely short half-life (the enzyme DPP-4 degrades GLP-1 rapidly following its release from gut cells) [Drucker 2006; Drucker 2001]. Much research has focused on compounds with molecular structures and incretin activity that are similar to GLP-1, but which have longer half-lives because they are not degraded by DPP-4 or are resistant to DPP-4. These compounds include exenatide and liraglutide, which are injectable treatments. Another approach is to identify compounds that inhibit the activity of DPP-4, thus prolonging the half-life of naturally occurring GLP-1. Two oral agents that act as DPP-4 inhibitors are sitagliptin and vildagliptin [Gallwitz, 2006]. REFERENCES Drucker DJ. Cell Metab . 2006;3:153-165. Drucker DJ. Curr Pharm Des . 2001;7:1399-1412. Gallwitz B. Eur Endocr Dis . June 2006:43-46.
  • Exenatide and first-phase insulin response in Type 2 diabetes Exenatide is a synthetic form of the naturally occurring peptide exendin-4, originally discovered in the salivary glands of the Gila monster. This 39-unit peptide shares a similar amino acid sequence with GLP-1, but unlike GLP-1, it is not degraded by the enzyme DPP-4. The half-life of exenatide is about 3 hours (compared with less than 5 minutes for GLP-1) [Fehse et al, 2005; Gallwitz, 2006; Meier et al, 2004]. One goal of this study was to assess both first- and second-phase insulin response in individuals with Type 2 diabetes (n=13) treated with exenatide or saline infusion compared with weight- and age-matched saline-infused (n=12) healthy individuals. All oral glucose-lowering medications were discontinued prior to the test, and an intravenous glucose bolus was administered to all participants [Fehse et al, 2005]. When an intravenous glucose challenge followed saline infusion, individuals with Type 2 diabetes, in comparison with healthy individuals, exhibited a sharply reduced insulin response in the first 10 minutes (first phase) and during the remainder of the study (second phase). In contrast, when the same individuals were infused with exenatide, their first-phase insulin response was higher compared with saline ( P <0.05) and similar to the healthy group. Second-phase insulin response was also increased with exenatide infusion compared with saline infusion in both individuals with Type 2 diabetes and healthy individuals ( P <0.001) [Fehse et al, 2005]. These results corroborate our understanding that an underlying cause of hyperglycaemia in Type 2 diabetes is an inadequate first- and second-phase insulin response resulting from reduced β-cell insulin secretion. They also show the promise of exenatide to compensate for this depressed insulin response. REFERENCES Fehse F, Trautmann M, Holst JJ, et al. J Clin Endocrinol Metab . 2005;90:5991-5997. Gallwitz B. Eur Endocr Dis . June 2006:43-46. Meier JJ, Nauck MA, Kranz D, et al. Diabetes. 2004;53:654-662.
  • Sitagliptin improves both fasting and post-meal glucose in monotherapy vs placebo Sitagliptin is an orally administered GLP-1-enhancing agent that is a highly selective inhibitor of the enzyme DPP-4 and has minimal inhibitory effects on other enzymes in the DPP family of enzymes. The first graph on this slide shows the results of a large-scale efficacy trial of sitagliptin monotherapy in individuals with Type 2 diabetes. The design included a 2-week placebo baseline period followed by a 24-week treatment that compared sitagliptin 100 mg once daily with placebo. No other oral glucose-lowering agents were used. Fasting plasma glucose decreased rapidly with sitagliptin compared with placebo (net decrease -1.0 mmol/l [-17.1 mg/dl], P <0.001). Meal tolerance tests were conducted both at baseline and following 24 weeks of sitagliptin treatment. The difference in post-meal glucose response compared with baseline in shown in the second graph. Sitagliptin treatment substantially reduced glucose at 1 and 2 hours post-meal (net decrease -2.6 mmol/l [-46.7 mg/dl], P <0.001). These results indicate that sitagliptin monotherapy improves glucose control in both the fasting and postprandial state. REFERENCE Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE, for the Sitagliptin Study 021 Group. Diabetes Care. 2006;29:2632-2637.
  • Sitagliptin added to metformin improves 24-hour glucose profile in Type 2 diabetes This study evaluated the efficacy of sitagliptin in combination with metformin in individuals whose hyperglycaemia was inadequately controlled by metformin alone. It has been posited that adding sitagliptin to metformin therapy may enhance glucose control by combining metformin’s insulin-sensitising effect with sitagliptin’s GLP-1 enhancement [Brazg et al, 2007; Gallwitz, 2006]. Study participants were treated with metformin plus placebo or sitagliptin 50 mg twice daily during a 4-week period; at the close of the study, each participant’s 24-hour glucose profile was measured [Brazg et al, 2007]. Sitaglitpin combined with metformin produced substantially lower glucose concentrations in both the postprandial and fasting states compared with metformin montherapy. The decrease in 24-hour mean glucose for the sitagliptin-treated group compared with metformin monotherapy was -1.8 mmol/l (-32.8 mg/dl) ( P <0.001) [Brazg et al, 2007]. These results demonstrate that the addition of sitagliptin to metformin improves glycaemic control compared with metformin monotherapy. REFERENCES Brazg R, Xu L, Dalla Man C, Cobelli C, Thomas K, Stein PP. Diabetes Obes Metab. 2007;9:186-193. Gallwitz B. Eur Endocr Dis . June 2006:43-46.
  • 2003 role of incretins in glucose homeostasis and diabetes

    1. 1. Mudasir bashir M.V.Sc.scholar DIV--.VSR Roll no.4856
    2. 2. Incretins <ul><li>Incretins are hormones having insulinotropic activity at usual physiological concentrations. </li></ul><ul><li>These are secreted from gut of animal after ingestion of nutrition[glucose or fat] </li></ul><ul><li>INCRETIN EFFECT:-insulin secretory response of incretins.. </li></ul><ul><li>It accounts for atleast 50% of the total insulin secreted after oral glucose. </li></ul>
    3. 3. Historical aspect <ul><ul><li>The concept of incretins is atleast a century old. </li></ul></ul><ul><li>In 1902 bayliss and starling published ”mechanism of pancreatic secretion”. </li></ul><ul><ul><li>---- chemical stimulus and not nervous system controls pancreatic secretion. </li></ul></ul><ul><ul><li>The chemical is secretin — inducing exocrine secretion. </li></ul></ul><ul><ul><li>They also considered the possibility of chemical excitent for internal secretion. </li></ul></ul>
    4. 4. <ul><li>Moore 1906 gave Intestinal extract----first attempt for diabetes treatment on incretin based. </li></ul><ul><li>In 1932,La Berre used the word ‘ incretin ’ to an extract from upper gut that produces hypoglycemia but doesn’t induce exocrine secretion.but he didn’t prove that incretins existed. </li></ul><ul><li>Insulin existence ------ radioimmunoassay. </li></ul>
    5. 5. <ul><li>Between 1964 to 1967 three groups{elrick et al,1964;mcintyre et al,1964;perley and kippins,1967}------ inc.insulin secretion on oral intake of glucose than i.v route. </li></ul><ul><li>In 1971,john c.brown isolated and deduced structure of a peptide isolated from intestinal mucosa---GIP. </li></ul><ul><li>insulinotropic properties---glucose dependent insulinotropic peptide[Gip] </li></ul><ul><li>GIP------first incretin to be isolated. </li></ul>
    6. 6. <ul><li>Another peptide in 1985 was found having potent insulinotropic activity{schemidt et al}—glucagon like peptide{GLP-1} </li></ul><ul><li>GIP and GLP-1--------together account for full incretin effect. </li></ul><ul><li>Only GLP-1 and not GIP could increase insulin secretion and normalise blood glucose in type2DM patients when given at supraphysiological levels. </li></ul><ul><li>Like GIP,GLP-1 also shows glucose dependence for its insulin secretory response. </li></ul>
    7. 7. Synthesis, secretion and degradation of incretins <ul><li>Glucose dependent insulinotropic peptide{GIP}:- </li></ul><ul><li>Synthesis :- gipgene---  153amino acid precursor----  GIP----- a member of a family of structurally related harmones—secretin,glucagon, and VIP </li></ul><ul><li>GIP is synthesised in and released in response to nutrients from enteroendocrine cells[k cells] . </li></ul>
    8. 8. <ul><li>K cells are primarily present in duodenum and jejunum. </li></ul><ul><li>Expression of gip gene in gut is regulated by nutrients. </li></ul><ul><li>glucose and lipid administration increases GIP mRNA levels in git. </li></ul><ul><li>Transcription factors like GATA-4,isl-1,PDX-1 and Pax2 are essential in cell specific expression of GIP within the k cells. </li></ul><ul><li>Rat salivary glands and lens epithelial cells also expresses gip gene. </li></ul>
    9. 9. <ul><li>Secretion:- dose dependent basis of nutrients. </li></ul><ul><li>varies among species—in humans lipid causes more secretion than carbohydrates.in pig and rodents secretion occurs more on carbohydrate intake. </li></ul><ul><li>GIP secretion coupling pathways are poorly understood.presumably there is increased intracellular calcium conc. </li></ul><ul><li>Some k cells also contain sweet receptors[GPCRS] and their activation by sugars and sweeteners lead to GIP secretion. </li></ul>
    10. 10. Degradation of GIP 1 2 3 42 GIP Des-HA-GIP (inactive) Enzymatic cleavage of GLP-1 by DPP-4 inactivates GLP-1 1 2 3 42 DPP-4 <ul><li>Two possible solutions to utilize GLP-1 action therapeutically: </li></ul><ul><li>Long-acting DPP-4-resistant GLP-1 analogues / incretin mimetics </li></ul><ul><li>DPP-4 inhibitors / incretin enhancers </li></ul>Mentlein et al. Eur J Biochem. 1993; Gallwitz et al. Eur J Biochem. 1994
    11. 11. <ul><li>GLUCAGON-LIKE PEPTIDE-1 :- synthesis:- </li></ul><ul><li>proglucagon gene. </li></ul><ul><li>Also encodes glucagon and GLP-2. </li></ul><ul><li>GLP-1 and GLP-2 are produced in enteroendocrine cells[l cells],scattered in small bowel and ascending colon. </li></ul><ul><li>Post transcriptional processing --- pc1/3 ,pc2 and furin which varies with tissues. </li></ul><ul><li>GUE and CRE----proglucagon gene expression. </li></ul>
    12. 12. <ul><li>Secretion:- </li></ul><ul><li>Primary physiological stimuli for secretion of GLP-1 are fat and carbohydrates. </li></ul><ul><li>Although GLP-1 also found in taste buds and brain but majority of GLP-1 seen in peripheral blood is from l cells. </li></ul><ul><li>Secretion of GLP-1 is also regulated by neural and endocrine signals. </li></ul><ul><li>Also GPCRs on l cells ----- free fatty acids and lipids------ increase in intracellular calcium and activation of mapk. </li></ul>
    13. 13. <ul><li>Degradation of GLP-1 </li></ul>Enzymatic cleavage of GLP-1 by DPP-4 inactivates GLP-1 DPP-4 7 8 9 Des-HA-GLP-1 (inactive) 7 8 9 <ul><li>Two possible solutions to utilize GLP-1 action therapeutically: </li></ul><ul><li>Long-acting DPP-4-resistant GLP-1 analogues / incretin mimetics </li></ul><ul><li>DPP-4 inhibitors / incretin enhancers </li></ul>
    14. 14. Secretion,effect and degredation
    15. 16. <ul><li>Incretin effect--GIP + GLP-1 </li></ul>Time (min) Insulin (mU/l) 60 120 180 Insulin (mU/l) Time (min) 0 60 120 180 Control subjects People with Type 2 diabetes Nauck et al. Diabetologia. 1986 80 60 40 20 0 Incretin effect Oral glucose load Intravenous glucose infusion
    16. 17. Incretin effect <ul><li>GIP:- almost lost in Type2DM </li></ul><ul><li>Loss of insulinotropic effect ----chronic desensitization of GIPRs or reduction in expressions of GIPRs on pancreatic cells. </li></ul><ul><li>Desensitization ----receptor internalization,down regulation and uncoupling from G-proteins. </li></ul><ul><li>Hyperglycaemia triggers the association of GIPR and ubiquitin ligase complexes--------reduction of GIPR protein levels and down-regulation of GIP action. </li></ul>
    17. 18. <ul><li>GLP- 1 : effects in humans </li></ul>After food ingestion… GLP-1 is secreted from L-cells of the jejunum and ileum That in turn… <ul><li>Stimulates glucose- dependent insulin secretion </li></ul><ul><li>Suppresses glucagon secretion </li></ul><ul><li>Slows gastric emptying </li></ul><ul><li>Leads to a reduction of food intake </li></ul><ul><li>Improves insulin sensitivity </li></ul>Long-term effects in animal models: <ul><li>Increase of β -cell mass and improved β -cell function </li></ul>After food ingestion…
    18. 19. Pleotropic effect of incretin in pancreas <ul><li>EFFECT ON ß-CELLS:- </li></ul><ul><li>GIP+GIPR---  increases insulin secretion </li></ul><ul><li>GIP also replenishes insulin in ß-cells-----increasing insulin gene transcription and biosynthesis. </li></ul><ul><li>EFFECT ON GLUCAGON SECRETION:- </li></ul><ul><li>GIP stimulates glucagon secretion via GIPR present on pancreatic alpha cells but under certain conditions. </li></ul>
    19. 20. GLUCAGON-LIKE PEPTIDE <ul><li>EFFECTS ON ß-CELLS:- GLP-1 stimulates insulin secretion via GLP-1R present on ß-cells. </li></ul><ul><li>GLP-1 replenishes ß-cell insulin stores and prevents exhaustion of ß-cell reserves via increased insulin mRNA stability,gene transcription and biosynthesis. </li></ul><ul><li>Effect on glucagon secretion:- </li></ul><ul><li>Inhibits glucagon secretion in euglycemic and hyperglycemic condition-somatostatin secretion </li></ul>
    20. 21. <ul><li>CENTRAL AND PERIPHERAL NERVOUS SYSTEM EFFECTS ON FOOD INTAKE AND GLUCOSE HOMEOSTASIS:- </li></ul><ul><li>Reciprocal systems “gut-brain axis”----regulate short and long term energy homeostasis. </li></ul><ul><li>GLP-1------key regulator of food intake,appetite and body weight. </li></ul><ul><li>GLP -1R agonist reduces short term food intake when injected peripherally or into CNS. </li></ul><ul><li>Prolonged use of GLP-1 agonists reduces both food intake as well as body weight. </li></ul>
    21. 22. <ul><li>GASTROINTESTINAL TRACT:- GLP-1 is potent inhibitor of several GIT functions like gastric acid secretion,gastric emptying and motility----decreasing nutrient absorbtion----decreasing blood glucose levels. </li></ul><ul><li>GLP-1 is important mediator of “ILEAL BRAKE EFFECT”---endocrine inhibition of upper GIT functions activated by presence of nutreints in the ileum. </li></ul><ul><li>Slowing of gastric emptying may be via neural mechanism. </li></ul>
    22. 23. <ul><li>Muscle,adipose tissue and liver:- </li></ul><ul><li>Insulin-like effect in major extrapancreatic tissues. </li></ul><ul><li>This helps in glucose homeostasis. </li></ul><ul><li>GLP-1 treatment mediated through inositol phosphogylcan generation. </li></ul>
    23. 24. Incretin therapy in type2DM
    24. 25. B-cell function and glucagon in T2DM β -Cell mass in Type 2 diabetes -50% -63% ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus Obese Lean
    25. 26. <ul><li>Hepatic </li></ul><ul><li>glucose </li></ul><ul><li>output </li></ul>Excessive hepatic glucose production in Type 2 diabetes Insulin; IR Glucagon Fasting & postprandial hyperglycaemia plasma glucose concentration. IR=insulin resistance
    26. 27. <ul><li>Insulin and glucagon dynamics in response to meals in normal subjects and Type 2 diabetes </li></ul>Type 2 diabetes Meal Delayed/depressed insulin response Nonsuppressed glucagon 20.0 18.3 16.6 15.0 13.3 6.1 4.4 140 130 120 110 100 90 120 90 60 30 0 Glucose (mmol/l) Insulin (mU/l) Glucagon (ng/l) Normal subjects
    27. 28. Action of glucagon Glycogen Glucose Low blood glucose and insulin promotes glucagon release from  - cells of pancreas Glucagon stimulates breakdown of glycogen Raises blood glucose
    28. 29. INCRETIN SECRETION IN TYPE 2 DM <ul><li>T2DM is characterised by a severely impaired or absent GIP insulinotropic effect that most likely results in worsening insulin secretion . </li></ul><ul><li>Note:-T2dm doesn’t result primarily from deficient incretin secretion. </li></ul><ul><li>Insulinotropic effect of GLP-1 is intact in T2DM and is used for its treatment. </li></ul><ul><li>GLP-1 based therapy for 3months in T2DM patients results in restoration of both first phase insulin secretion as well as late-phase secretion. </li></ul>
    29. 30. Postprandial GLP-1 levels are decreased in people with IGT and Type 2 diabetes 2001 Time (min) GLP-1 (pmol/l) * * * * * * * * Meal NGT T2DM IGT * P <0.05 T2DM vs NGT Toft-Nielsen et al. J Clin Endocrinol Metab. 20 15 10 5 0 0 60 120 180 240
    30. 31. 16 12 8 4 0 2200 0200 0600 1000 1400 1600 Breakfast Lunch Snack Clock time (hours) Glucose (mmol/l) T2DM + GLP-1 Normalisation of diurnal plasma glucose concentrations by continuous IV GLP-1 infusion (1.2 pmol/kg/min) Rachman et al. Diabetologia. 1997 T2DM
    31. 32. <ul><li>GLP-1 preserves human islet morphology and function in cultured islets in vitro </li></ul>Day 1 Day 3 Day 5 Control + GLP-1 Farilla et al. Endocrinology. 2003
    32. 33. <ul><li>Effect of GLP-1 on β -cell mass in Zucker diabetic fatty rats </li></ul>Control GLP-1 treated β -Cell mass (mg) 16 12 8 4 0 β-Cell mass Proliferating β-cells (%) 2.5 2.0 1.5 1.0 0.5 0 Control GLP-1 treated 30 20 10 0 Control GLP-1 treated β-Cell apoptosis β-Cell proliferation Apoptotic β-cells (%) Farilla et al. Endocrinology. 2002
    33. 34. GLP-1 enhancement GLP-1 secretion is impaired in Type 2 diabetes Natural GLP-1 has extremely short half-life <ul><li>Add GLP-1 analogues with longer half-life: </li></ul><ul><ul><li>exenatide </li></ul></ul><ul><ul><li>liraglutide </li></ul></ul>Injectables <ul><li>Block DPP-4, the enzyme that degrades GLP-1: </li></ul><ul><ul><li>sitagliptin </li></ul></ul><ul><ul><li>vildagliptin </li></ul></ul>Oral agents
    34. 35. <ul><li>EXENATIDE:-[Byetta] </li></ul><ul><li>It is a synthetic EX-4[39 amino acid] produced in the salivary glands of Gila monster lizard[Haloderma suspectum]. </li></ul><ul><li>It is not substrate for DPP4 ----GLY in place of ALA. </li></ul><ul><li>It lacks target bonds for neutral endopeptidaseNET. </li></ul><ul><li>Its sec. and tertiary str.------prevents NET </li></ul><ul><li>thus has long biological activity. </li></ul><ul><li>No specific receptors are available for its action in Gila monster. </li></ul><ul><li>It has greater affinity for GLP-1R than GLP-1 in GLP-1R expressing cells. </li></ul>
    35. 36. <ul><li>It is given subcutaneously [bid]. </li></ul><ul><li>It has biological activity of 8hr. </li></ul><ul><li>It has 5000 fold greater potency than GLP-1 in reducing blood glucose. </li></ul><ul><li>It delays gastric emptying both non-diabetic as well as diabetic.. </li></ul><ul><li>It can best be used with sulfonylureas. </li></ul><ul><li>Its side effects are---nausea,vomiting and rarely hypoglycemia. </li></ul><ul><li>Now Exenatide LAR can be used ----once a week. </li></ul><ul><li>It has beneficial effect in osteopenia. </li></ul>
    36. 37. Exenatide and first-phase insulin response in Type 2 diabetes Type 2 diabetes,placebo Type2 diabetes,exenatide Healthy subjects, placebo Fehse et al. J Clin Endocrinol Metab . 2005 Exenatide vs healthy Time (min) Insulin secretion (pmol•kg -1 •min -1 )
    37. 38. <ul><li>SITAGLIPTIN:-[januvia] </li></ul><ul><li>it is the sole DPP4 inhibitor in use for T2DM. </li></ul><ul><li>It is used as non-peptide oral based therapy for T2DM. </li></ul><ul><li>Its selective inhibitor of DPP4 and donot interact with closely related proteases. </li></ul><ul><li>Its biological half life is 8-14hr and its bioavailability is 87% in absence or presence of food. </li></ul><ul><li>Appx 80% is excreted unchanged and rest is metabolised by CYP3A4 and CYP2C8 in liver. </li></ul><ul><li>Adverse effects-----headaches,nasopharyngites,contact dermatites and arthralgia. </li></ul><ul><li>It also has beneficail effect in osteopenia.—thyroid secretion. </li></ul>
    38. 39. <ul><li>The main drawback of using DPP4 inhibitors ---------------decrease incretin secretion------------inhibition of glucose lowering effect. </li></ul><ul><li>Metformin and DPP4 have better effect in reducing blood glucose levels.----metformin increases GLP-1 secretion. </li></ul><ul><li>Dosage-100mg daily.in increased creatinin dose should be reduced to half[ <50mg creatinine clearence]. </li></ul>
    39. 40. Sitagliptin improves fasting glucose level in monotherapy vs placebo Plasma glucose (mmol/l) Time (weeks) 0 6 12 3 18 24 Placebo Sitagliptin 100 mg 9.0 9.5 8.5 10.0 10.5 8.0 Charbonnel et al. Diabetes Care. 2006; R osenstock et al. Clin Ther. 2006
    40. 41. Sitagliptin added to metformin [janumet]improves 24-hour glucose profile in Type 2 diabetes Glucose (mmol/l) 8:00 Day 1 13:00 19:00 0:00 Day 2 7:30 6 7 8 9 10 13 11 12 Dose 1 7:30 Dose 2 18:30 Breakfast Lunch Dinner Placebo + metformin Sitagliptin 50 mg bd + metformin Time
    41. 42. Therapies under development. <ul><li>VIDAGLIPTIN:- </li></ul><ul><li>DPP4 inhibitor. </li></ul><ul><li>Achieves plasma peak conc. Within 1-2hr. </li></ul><ul><li>Half life is shorter than sitagliptin[by 1-2hr]. </li></ul><ul><li>It is metabolised in liver. </li></ul><ul><li>Can be given in kidney patients at normal dose. </li></ul><ul><li>Not approved yet by FDA but by european medicines agency. </li></ul>
    42. 43. <ul><li>LIRAGLUTIDE: - </li></ul><ul><li>Potent GLP-1 analog with substitution of lys with arg and attachment of C-16 free fatty acid to lys. </li></ul><ul><li>It increases it half life as it gets bind with plasma albumin. </li></ul><ul><li>Also injected S.C and half life is 11-13hr. </li></ul><ul><li>Side effects:-nausea,vomiting,and pancreatites </li></ul>
    43. 45. <ul><li>Why to go for incretin therapy??? </li></ul><ul><li>Lowers blood glucose levels. </li></ul><ul><li>Prevent deterioration of ß-cells. </li></ul><ul><li>Leads to weight loss. </li></ul><ul><li>Decreasing release of glucagon. </li></ul><ul><li>Delaying gastric emptying. </li></ul><ul><li>Restoring first-phase and second phase insulin secretion. </li></ul><ul><li>Decreasing food intake. </li></ul>