GLP-1 and Diabetes Mellitus

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GLP-1 and Diabetes

Dr. Shashikiran UmakanthProf & Head, MedicineDr. TMA Pai Hospital, UdupiMMMC, Manipal University

Microvascular changesMacrovascular changesKendall DM, et al. Am J Med 2009;122:S37-S50.Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343.Relative Changes

-cell failure

Years

-10-5051015202530

Insulin resistanceInsulin level050100150200250

-15

b-cell function

OnsetdiabetesGlucose (mg/dL)

Diabetesdiagnosis

50100150200250300350

Fasting glucose

Prediabetes (Obesity, IFG, IGT)

Postmeal Glucose-10-5051015202530-15YearsNatural history of type 2 diabetes

CaseA 58-year-old gentleman, Mr Kumar, a building contractor withType 2 diabetesHypertensionObesityRecurrent balanoposthitis

Mr KumarHe is on treatment withMetformin 1000mg 1-0-1Enalapril 10mg 1-0-0Rosuvastatin 0-0-1Vitamin supplements

Complains ofNocturiaDiscomfort while passing urineAbdominal bloating - gasHas very irregular eating habits

ExaminationGen exam - normal except abd obesityEyes - normalCVS & RS - normalAbdomen - normalNervous system - absent ankle reflexesPulse - 80/min, regularBP 130/80Weight - 84 kgBMI - 30.8Mr Kumar

InvestigationsFBS - 150PPBS - 265HbA1c - 8.7%Creatinine - 1.2Potassium - 4.1LFT - normal

Lipid profileCholesterol - 230Triglycerides - 215HDL - 32LDL - 155Urine8 WBCs/HPFMr Kumar

Kumar doesnt want to take an injection. Which antidiabetic would you add to metformin?SulfonylureaPioglitazoneDPP-4 inhibitorVogliboseSGLT-2 inhibitorBromocriptineMr Kumar

In patients with type 2 diabetes and inadequate glycaemic control on metformin monotherapy, the addition of sitagliptin or glimepiride led to similar improvement in glycaemic control after 30 weeks.

Sitagliptin was generally well tolerated. Compared to treatment with glimepiride, treatment with sitagliptin was associated with a lower risk of hypoglycaemia and with weight loss versus weight gain

Treatment with metformin plus vildagliptin compared with metformin plus sulphonylurea is expected to result in a lower incidence of diabetes-related adverse events and to be a cost-effective treatment strategy.

Started onVildagliptin 50mg 1-0-1 Rosuvastatin 20mg 0-0-1Metformin and Enalapril continued

Balanoposthitis treated

Mr Kumar - Progress

Glucagon-like peptide 1 (GLP-1)

GLP-1An incretin (hormone that increases insulin secretion in response to a meal)30-amino acid peptide secreted in response to the oral ingestion of nutrients by intestinal L cellsGLP-1 receptors (GLP-1R) are located in islet cells, central nervous system, and other organsGLP-1 is metabolized by the enzyme dipeptidyl peptidase-4 (DPP-4)

Serum Insulin

Time (min)

Incretin Effect

**

*****

Oral Glucose Intravenous Glucose(Isoglycemic)

60120 180

0

Adapted from Circulation. 2011; 124: 2285-2289First described in New Interpretation of Oral Glucose Tolerance. Lancet. 1964 Jul 4;2(7349):20-1.A phenomenon whereby a glucose load delivered orally produces a much greater insulin secretion than the same glucose load administered intravenously

Numerous functions of GLP-1

Stomach: Helps regulate gastric emptyingPromotes satiety and reduces appetite

Liver: Glucagon reduces hepatic glucose outputBeta cells:Enhances glucose-dependent insulin secretion

Alpha cells: Glucose-dependent postprandialglucagon secretion

Data from Flint A, et al. J Clin Invest 1998;101:515-520. Data from Larsson H, et al. Acta Physiol Scand 1997;160:413-422.Data from Nauck MA, et al. Diabetologia 1996;39:1546-1553. Data from Drucker DJ. Diabetes 1998;47:159-169.

GLP-1: Secreted upon the ingestion of food

GLP-1 preserves human islet cell morphology and function in cultured islets in vitroDay 1Day 3Day 5ControlGLP-1 treatedFarilla et al. Endocrinology. 2003 Dec;144(12):5149-58

Comparison of incretinsYesYesPromotes insulin biosynthesisNoYesReduces food intakeNoYesDecreased secretion in T2DMYesYesKnockout mice (result in IGT)YesYesStimulates beta-cell mass/growthNoYesSlows gastric emptyingNoYesInhibits glucagon secretion postprandiallySite of ProductionGIPK-cells(Duodenum and Jejunum)GLP-1L-cells(Ileum and Colon)

Microvascular changesMacrovascular changesKendall DM, et al. Am J Med 2009;122:S37-S50.Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343.Relative Changes

-cell failure

Years

-10-5051015202530

Insulin resistanceInsulin level050100150200250

-15

b-cell function

OnsetdiabetesGlucose (mg/dL)

Diabetesdiagnosis

50100150200250300350

Fasting glucose

Prediabetes (Obesity, IFG, IGT)

Postmeal Glucose-10-5051015202530-15YearsNatural history of type 2 diabetesIncretin effect

Incretin effect is blunted in type 2 diabetesInsulin (mU/L)Time (min)Healthy SubjectsInsulin (mU/L)Time (min)Type 2 DiabetesN = 22; Mean (SE); *P0.05 Data from Nauck M, et al. Diabetologia 1986;29:46-52.

020406080060120180

020406080060120180

Intravenous (IV) GlucoseOral Glucose

Reduced Incretin EffectIncretin Effect

*******

***

The greater beta-cell response observed in subjects with type 2 diabetes during intravenous glucose administration is due to the higher glucose stimulus in subjects with diabetes.

GLP-1 has a short half-life - 2 minGluGlyThrPheThrSerAspLysAlaAlaGlnGlyGluLeuTyrSerIleAlaTrpLeuValLysGlyArgGlyValSerGluPheLysDPP-4HisAla7379

GLP-1 is inactivated by DPP-IV by N-terminal degradation of the peptide at position 2 alanine.GLP-1 half-life in man is in the order of 1-2 min with a high clearance of 4-10 L/min.

Therapeutic potential of GLP-1How do we leverage it?

HbA1c Goals unmet in most

AACE/ACE recommended target (9%12.4% have A1C >10%

64.2% of patients with type 2 diabetes have A1C 7%

Contribution of PPBS to HbA1c

% ContributionHbA1c Range (%)020406080100

FPG (Fasting Plasma Glucose)PPG (Postprandial Plasma Glucose)>10.2

70%30%9.3-10.2

60%40%8.5-9.2

55%45%7.3-8.4

50%50%