Dr Wayne Riback Senior Medical Advisor Diabetes Mellitus Dr Wayne Riback Senior Medical Advisor

Diabetes is an increasing healthcare epidemic throughout the world Global projections for the number of people with diabetes (20–79 age group), 2007–2025 (millions) 53.2 64.1 +21% 28.3 40.5 +43% 67.0 99.4 +48% South and Central America Africa Eastern Mediterranean and Middle East Europe North America South-East Asia Western Pacific 24.5 44.5 +81% 46.5 80.3 +73% The IDF found that, as a global phenomenon, the prevalence of diabetes is predicted to increase from 246 million in 2007 to 380 million by 2025, an increase of 55%.1 T2DM alone has reached epidemic proportions and affects approximately 5.9% of adults worldwide. The prevalence is increasing steadily and is expected to affect 7.1% of adults by the year 2025. In particular, the increase in T2DM is seen among younger people and in developing countries. Indeed, a disproportionate number of diabetic patients live in the Asia-Pacific region; approximately 81 million people with diabetes live in India and China compared with 19 million in the USA.1 In summary, these data provide an updated quantification of the current and growing public health burden of diabetes across the world. The human and economic costs of this epidemic have severe implications for healthcare resource use. Reference International Diabetes Federation. Diabetes Atlas 3rd Edition (2006): Page 5 10.4 18.7 +80% 16.2 32.7 +102% Worldwide: 246 million people in 2007 380 million projected for 2025 IDF. Diabetes Atlas 3rd Edition – 2006

Diabetes prevalence in the Middle East and Africa is high and increasing Prevalence rates and numbers of adults with diabetes (1,000s) Pakistan 2007: 8.3% – 6,929 2025: 8.5% – 11,538 Tunisia Lebanon Morocco Israel Iran Algeria Egypt Saudi Arabia Iran 2007: 6% – 2,565 2025: 8.4% – 5,115 Pakistan Saudi Arabia 2007: 13.5% – 1,855 2025: 15.7% – 3,610 Morocco 2007: 7.1% – 1,360 2025: 9.1% – 2,396 Lebanon 2007: 7.4% – 167 2025: 9.1% – 267 Algeria 2007: 7.3% – 1,475 2025: 8.9% – 2,528 Global data from the IDF Diabetes Atlas 3rd Edition show that the prevalence of diabetes (T1DM and T2DM) in adults (age >20 years) in the Middle East and Africa is high and is set to increase dramatically during the next 18 years.1 The greatest increase in prevalence will occur in Saudi Arabia (13.5–15.7%), Egypt (10.1–12.2%), with Iran (6.0–8.4%) and Morocco (7.1–9.1%) also markedly increasing their prevalence rates. In terms of the population developing diabetes, Iran and Saudi Arabia will see their diabetes population increasing by approximately 100%. Reference International Diabetes Federation. Diabetes Atlas 3rd Edition (2006). Israel 2007: 7.8% – 337 2030: 8.5% – 495 Tunisia 2007: 4.8% – 317 2025: 6.2% – 535 South Africa South Africa 2007: 4.5% – 1,213 2025: 4.4% – 1,279 Egypt 2007: 10.1% – 4,357 2025: 12.2% – 7,650 IDF. Diabetes Atlas 3rd Edition – 2006

How is South Africa performing with respect to DM Practices? Diabetes Action Now Booklet – Adapted from Wild S. Diabetes care 27: 1047-1053; 2004

Patients are uncontrolled with respect to HbA1c 100 69.4 % of patients HbA1c>7% HbA1c<7% 30 Table 33 Figures are given here as examples…. 30.4 South Africa

Patients uncontrolled with respect to HbA1c 100 38.2 60 % of patients HbA1c>8.4% HbA1c<7% HbA1c 7%- 8.4% 31.4 30 Table 33 Figures are given here as examples…. 30.4 South Africa

Type 2 DM Patients are not adequately screened for complications Percentage of patients who have never been screened in the last 12 months 45 35 25 South Africa 15 Screening of complications: Has your patient never been screened for …during the last 12 months ? We did not ask for the type of examination (clinical vs. ECG vs. lab testing etc.) for each. For example, as far as neurologic complications are concerned, we do not know if the absence of screening of neurologic complications means only the absence of physical examination (filament) or of nerve conduction testing. Tables 318a-f Figures are given here as examples…. 5 5.8 8.2 5.9 6.9 5.6 3.1 Cardio Vascular disease Eye Nerve Kidney Diabetic Foot ulcer Lipid

Type 2 DM Patients with complications Percentage of patients who have diabetes complications 45 35 25 South Africa 19 15 17 Screening of complications: Has your patient never been screened for …during the last 12 months ? We did not ask for the type of examination (clinical vs. ECG vs. lab testing etc.) for each. For example, as far as neurologic complications are concerned, we do not know if the absence of screening of neurologic complications means only the absence of physical examination (filament) or of nerve conduction testing. Tables 48-53 Figures are given here as examples…. 14 12 5 8 4 Coronary Artery disease Eye Nerve Kidney Diabetic Foot ulcer PVD

T2 DM: Only few patients have an HbA1c tested every 6 Months 100 90 99% 80 70 60 % of patients South Africa 50 40 30 41% 20 Table 33 Figures are given here as examples 10 2% In the last 12 months Every 6 months Every 3 months

The burden of diabetes on healthcare systems Diabetes accounts for between 5% and 10% of any nation’s health budget Three times the healthcare resources are being spent on treating diabetes complications compared with that spent on controlling diabetes before the onset of complications The cost of type 2 diabetes in Europe (CODE-2) study evaluated more than 7,000 patients with type 2 diabetes in eight European countries: Belgium, France, Germany, Italy, The Netherlands, Spain, Sweden and the UK The average yearly cost per patient was €2,834, the greatest proportion of which was accounted for by hospitalization costs Reference Jonsson B. Diabetologia 2002;45:S5–S12 CODE-2: cost of type 2 diabetes in Europe Jonsson B. Diabetologia 2002;45:S5–S12 Status of diabetes management

Pathogenesis of type 2 diabetes mellitus

Insulin-glucose profile after meal Breakfast Lunch Dinner Plasma insulin 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time

Type 2 diabetes mellitus (T2DM) requires progressive therapy T2DM is a progressive disease characterised by increased insulin resistance and decreasing pancreatic β-cell function1 At diagnosis, patients may have already lost approximately 50% of β-cell function2 An ideal treatment regimen for T2DM should provide: Continuity of care as the disease progresses Flexibility to adapt to individual needs Type 2 diabetes mellitus (T2DM) develops because of a progressive decline in pancreatic -cell function and decreasing insulin sensitivity in peripheral tissues. The -cells may compensate for peripheral insulin resistance by increasing insulin output. Eventually the -cells fail to produce sufficient insulin, and hyperglycaemia and diabetes ensue. During insulin resistance, increased hepatic glucose production and reduced glucose uptake by skeletal muscle both contribute to hyperglycaemia. Insulin also fails to suppress lipolysis in adipose tissue, resulting in increased concentrations of circulating free fatty acids (FFAs). FFAs stimulate gluconeogenesis, triglyceride synthesis and glucose production in the liver, and further impair glucose utilisation by skeletal muscle. Excess circulating glucose and FFAs act on cells and tissues to inhibit insulin secretion and action. This is referred to as gluco-lipotoxicity. The progressive nature of T2DM requires a progressive treatment strategy. Reference Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995–1015. Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995―1015. Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5.

Decreasing -cell function as part of the progression of T2DM 100 Time of diagnosis ? 80 60 Normal -cell function by HOMA (%) Pancreatic function ~50% of normal 40 20 ―10 ―8 ―6 ―4 ―2 2 4 6 Six-year follow-up data from the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated the decline in -cell function as T2DM progresses. At the time of diagnosis, -cell function is already reduced by approximately 50% and continues to decline regardless of therapy. Severe -cell failure results in insulin deficiency and a subsequent requirement for insulin therapy. Reference Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5. Time (years) HOMA=homeostasis model assessment Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5.

Multiple factors may drive progressive decline of b-cell function Hyperglycaemia (glucose toxicity) Insulin resistance b-cell (genetic background) Protein glycation “lipotoxicity” elevated FFA,TG External factors that influence the function of the beta cells ( there has been a lot of data published by Roger Unger on the effects of lipotoxicity Amyloid deposition

Both FBG and PPBG contribute to overall hyperglycaemia Onset of diabetes 350 300 250 200 150 100 50 19.4 16.7 13.9 11.1 8.3 5.5 2.8 PPBG Plasma glucose (mg/dl) FBG Plasma glucose (mmol/l) 250 200 150 100 50 Relative -cell function (%) Insulin resistance Insulin level -cell failure Obesity IGT T2DM Uncontrolled hyperglycaemia Clinical features Risk for diabetes complications with uncontrolled hyperglycaemia T2DM is a progressive disease characterised by declining pancreatic -cell function leading to decreased insulin levels. -cell dysfunction begins some 10–12 years before diabetes is diagnosed. Typically, by the time of diagnosis, approximately 50% of -cell function has already been lost.1 When the secretion of insulin cannot keep pace with the underlying insulin resistance, impaired glucose tolerance (IGT) and T2DM develop. The natural progression of T2DM is prolonged; many key features such as insulin resistance and macrovascular changes occur before hyperglycaemia develops and before T2DM is diagnosed.2 Exposure to metabolic dysregulation substantially increases the risk of developing macrovascular (e.g. stroke, ischaemic heart disease and peripheral vascular disease) and microvascular (e.g. retinopathy, nephropathy and neuropathy) complications at a later date.2 References Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5. Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995–1015. Years –10 –5 0 5 10 15 20 25 30 FBG=fasting blood glucose; IGT=impaired glucose tolerance; PPBG=postprandial blood glucose. Adapted from Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995―1015.

24-hour plasma glucose profile in T2DM and healthy subjects 400 20 T2DM 300 15 Plasma glucose (mg/dl) 200 Plasma glucose (mmol/l) 10 100 5 Healthy subjects Meal Meal Meal 06:00 10:00 14:00 18:00 22:00 02:00 06:00 In patients with T2DM, excess exposure to hyperglycaemia is linked to an increase in fasting plasma glucose concentration. Specifically targeting fasting hyperglycaemia will, therefore, lower the entire 24-hour plasma glucose profile and should be the primary aim of therapy. Reference Hirsch IB, et al. Clin Diabetes 2005;23:78–86. Time of day (hours) Comparison of 24-hour plasma glucose levels in healthy subjects vs patients with diabetes (p<0.001). Adapted from Hirsch I et al Clin Diab 2005;23:78-86

Guidelines provide HbA1c, FBG and PPBG targets Normal ADA/EASD1&3 Targets for Diabetic Patients AACE4 IDF5 SEMSDA HbA1c* (%) <6.01 <7.0† 6.5 <6.5 <7.0 FBG, mmol/l (mg/dl) <5.52 (<100) 3.97.2 (70130) 6.0 (110) <6.0 (<110) <7.0 (<130) PPBG, mmol/l (mg/dl) <7.8**1 (<140) <10.0** (<180) 7.8** (140) <8.0** (<145) <8.0 (<145) *DCCT referenced assays: normal range 4–6%; **1–2 hours postprandial; †ADA/EASD guidelines recommend HbA1c levels as close to normal (<6%) as possible without significant hypoglycaemia1,5 AACE=American Association of Clinical Endocrinologists; ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes; IDF=International Diabetes Federation The most recent HbA1c target set by the American Diabetes Association (ADA) is <7%, with the aim of restoring HbA1c to normal values (<6%) without significant hypoglycaemia.1 A consensus statement from the ADA and the European Association for the Study of Diabetes (EASD) recommends that an HbA1c value 7% should prompt the initiation or adjustment of treatment. The goal of treatment should be to achieve an HbA1c value as close to the healthy range (<6%) as possible or, at a minimum, decrease HbA1c to <7%.2 The ADA and EASD recognise that this goal is not appropriate or practical for some patients, and advocate an assessment of the potential risks and benefits of an intensified regimen for each individual patient.2 References 1. ADA. Diabetes Care 2006;29(suppl 1):S4–42. 2. Nathan DM, et al. Diabetologia 2006;49:1711–21. ADA. Diabetes Care 2006;29(suppl 1):S4–S42. ADA. Diabetes Care 2006;29(suppl 1):S43–8. ADA/EASD Consensus Algorithm - Nathan DM, et al. Diabetologia 2006;49:1711–21 AACE. Endocr Pract 2002;8(suppl 1):40–82. IDF. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation, 2005. http://www.idf.org/webdata/docs/IDF%20GGT2D.pdf.

SEMSDA Guidelines 2009

(insulin sensitisers) T2DM is a progressive condition Metformin (insulin sensitisers) Lifestyle changes Insulin Secretagogue Post Meal Glucose Glucose (mg/dL) Fasting Glucose Insulin Resistance Normal Function % of Insulin Level At risk for DM Beta cell dysfunction Years of Diabetes Risk for diabetes complications Adapted from: UKPDS 33: Lancet 1998; 352, 837-853 DeFronzo RA. Diabetes. 37:667, 1988. Saltiel J. Diabetes. 45:1661-1669, 1996. Robertson RP. Diabetes. 43:1085, 1994. Tokuyama Y. Diabetes 44:1447, 1995. Polonsky KS. N Engl J Med 1996;334:777. ©2000 International Diabetes Center. All rights reserved

The most powerful agent we have to control glucose Insulin The most powerful agent we have to control glucose

Balancing Good Glycemic Control with a Low Risk of Hypoglycemia… Key Point Essentially, the key to good insulin therapy is to balance good glycemic control with a low risk of hypoglycemia. Hypoglycemia 24

Imagine consulting room on Monday with the following: 59 years old male working as a financial manager – sedentary work most of the times during the week – works long hours. Over week-ends he enjoys hiking Type 2 diabetes diagnosed 12 years ago He has hypertension, dyslipidaemia.

Case study (continued) Current medication: Glimepiride 4 mg/day Metformin 1g bd Irbesartan 300 mg/day Rosuvastatin 10 mg/day Disprin CV 1/day

Case study (continued) Body mass index = 30 Waist circumference = 104.5 cm BP = 120/74 mm Hg No diabetes complications HbA1c = 8.9% FBG of 9-10 mmol/l PPBG up to 15 mmol/l

What will be prescribed? More than 200 combinations of insulin and oral agents are possible: Intensified insulin – basal-bolus or MDI Basal-plus Conventional – premix Basal-oral Basal – Glargine, Detemir, NPH Bolus – Glulisine, Lispro, Aspart, Human Regular, Premix- Regular or Rapidacting bolus component Different % combinations

Relative contribution of FBG and PPBG to HbA1c The relative contribution of PPBG is predominant in subjects with moderate diabetes, whereas the contribution of FBG increases as diabetes worsens 60 Postprandial Fasting 40 Relative contribution of FBG vs PPBG (%) 20 This study analysed the daytime glycaemic profiles of 290 individuals with T2DM controlled by diet or oral hypoglycaemic agents (OHAs).1 Blood-glucose concentrations were determined during fasting and postprandial periods. Fasting blood glucose (FBG) and post-prandial PPBG contribute to overall hyperglycaemia in individuals with T2DM to varying degrees according to HbA1c levels. In individuals with poor glycaemic control (HbA1c >7%) the relative contribution of FBG is greater than that of PPBG.2 PPBG is the major contributor when HbA1c is near to target. References Monnier L, et al. Diabetes Care 2003;26:881–5. Monnier L, et al. Diabetes Care 2002;25:737–741. <7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2 HbA1c (%) Adapted from Monnier L, et al. Diabetes Care 2003;26:881–5.

Plasma glucose (mg/dl) Plasma glucose (mmol/l) Treating fasting hyperglycaemia lowers the entire 24-h plasma glucose profile Hyperglycaemia due to an increase in fasting glucose 400 T2DM 20 300 15 Plasma glucose (mg/dl) 200 Plasma glucose (mmol/l) 10 Normal 100 5 Meal Meal Meal 06.00 10.00 14.00 18.00 22.00 02.00 06.00 In patients with T2DM, excess exposure to hyperglycaemia is caused by an increase in fasting plasma glucose concentration. Specifically targeting fasting hyperglycaemia will, therefore, lower the entire 24-hour plasma glucose profile and should be a primary aim of therapy. References Hirsch IB, et al. Clin Diabetes 2005;23:78–86. Time of day (hours) Comparison of 24-hour glucose levels in control subjects versus patients with diabetes (p<0.001). Adapted from Polonsky K, et al. N Engl J Med 1988;318:1231―1239. Copyright © 2007 Massachusetts Medical Society. All rights reserved. 30

INSULIN TACTICS Twice Daily Split–Mixed Regimens Regular Lispro Lispro Lispro Insulin Effect Reg Reg Insulin Effect NPH NPH NPH NPH B L S HS B B L S HS B Meals Meals

Case study Max OAD HbA1c = 8.9% FBG of 9-10 mmol/l PPBG up to 15 mmol/l Hb

More physiologic insulin replacement = Basal – Bolus/ Basal-Plus

Type 2 DM Rx Strategies : ‘Basal-Plus’ therapy FBG <6mM but HbA1c >7.0% (>6.5%) introduce Glulisine before meal with max BG excursion >7.8mM (>10mM) 12 OHAs + glargine 8 Glucose (mmol/l) 4 Glulisine* 8 12 18 22.00 hrs Breakfast Lunch Snack Dinner glargine Metformin no change (2g/d) Glimepiride, gliclazide SR no change, Glibenclamide, gliclazide no change, reduce or stop pre-dinner dose Meglitinides need to stop pre-dinner dose *Start Glulisine 4 units based on SMBG if PPBG >/=7.8 mM Titrate upwards by 2 units every 5-7 days to achieve PPBG <7.8mM 34

Insulin treatment options in type 2 diabetes Basal Plus therapy long-acting insulin + rapid acting analog with 1-2 meals +/- oral agents Conventional Insulin Therapy 2-3 injections mix of regular insulin / rapid-acting insulin analog and long-acting insulin Prandial / Intensified Insulin Therapy Short acting insulin or rapid insulin analog prandially + long-acting insulin Basal insulin therapy Long-acting insulin +/- oral agents

Insulins Class of insulin Product Action onset Action duration Peak/max Human Insulins Shortacting Actrapid Humulin R 30 min 8 hrs 2.5-5hrs Intermediate-acting: Isophane Zinc suspension Humulin N Protaphane Humulin L 1.5hr 2.5 hrs 16hrs 20hrs 4-12hrs 7-15hrs Biphasic/Premixed Actraphane (30/70) Humulin 30/70 Mixtard 20/80 24 hrs 2-12 hrs Inhaled Insulins Exubera* Analogue insulins Ultra shortacting Humalog Novorapid Glulisine* 10-20 min 3-5 hrs 1-3 hrs Intermediate-acting Detemir 14 hours (hypoglycaemic effect 6-8 hours Biphasic/premixed Humalog mix 25 Novomix 30 15-18 hrs 1-4hrs Longacting Lantus (Glargine) 1 hr 24 hrs No peak

Onset and Duration of Insulin Preparations Gummerson, Irene. Insulin analogues revisited, Hospital Pharmacist, April 2003, vol. 10, p.165 - 172

The Ideal Basal Insulin … Mimics normal pancreatic basal insulin secretion Long-lasting effect Smooth peakless profile Reproducible and predictable effects Reduced nocturnal hypoglycemia Once-daily administration for convenience Pharmacodynamic effects similar to insulin pump

Plasma insulin (U/mL) Basal/Bolus Treatment Program with Rapid-Acting and Long-Acting Analogs 75 Breakfast Lunch Dinner Aspart or Lispro Aspart or Lispro Aspart or Lispro 50 Plasma insulin (U/mL) 25 Glargine Basal/Bolus Treatment Program with Rapid-Acting and Long-Acting Analogs This is ideal therapy. Most patients are unwilling or unable to take 4 injections per day, which brings us to the rationale for NovoLog® Mix 70/30. Time 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Verbal communication from Bode, BW. Atlanta, Ga; Feb. 2003.

Current Strategies for Improving the Therapeutic Potential of GLP-1 Agents that mimic the actions of GLP-1 (incretin mimetics) DPP-IV–resistant GLP-1 derivatives (dipeptidyl peptidase) Examples: GLP-1 analogues, albumin bound GLP-1 Novel peptides that mimic some of the glucoregulatory actions of GLP-1 Exenatide - Victoza (NovoNordisk) - Syncria (GSK – Phase II) Agents that prolong the activity of endogenous GLP-1 DPP-IV Inhibitors Drucker DJ, et al. Diabetes Care. 2003;26:2929-2940.; Baggio LL, et al. Diabetes. 2004;53:2492-2500.

GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins Promotes satiety and reduces appetite Alpha cells: ↓ Postprandial glucagon secretion DISCUSSION By decreasing β-cell workload and improving β-cell response, GLP-1 is an important regulator of glucose homeostasis. Upon food ingestion, GLP-1 is secreted into the circulation. GLP-1 increases β-cell response by enhancing glucose-dependent insulin secretion. BACKGROUND GLP-1 is secreted from L cells of the small intestine. GLP-1 decreases β-cell workload, hence the demand for insulin secretion, by: Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (β-cell workload) Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on β-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake Effect on Beta cell: Drucker DJ. Diabetes. 1998;47:159-169. Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand. 1997;160:413-422. Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997;160:413-422. Effects on Stomach: Nauck MA, et al. Diabetologia. 1996;39:1546-1553. Effects on CNS: Flint A, et al. J Clin Invest. 1998;101:515-520. Liver: ↓ Glucagon reduces hepatic glucose output Beta cells: Enhances glucose-dependent insulin secretion Stomach: Helps regulate gastric emptying Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.

GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins Promotes satiety and reduces appetite Alpha cells: ↓ Postprandial glucagon secretion DISCUSSION By decreasing β-cell workload and improving β-cell response, GLP-1 is an important regulator of glucose homeostasis. Upon food ingestion, GLP-1 is secreted into the circulation. GLP-1 increases β-cell response by enhancing glucose-dependent insulin secretion. BACKGROUND GLP-1 is secreted from L cells of the small intestine. GLP-1 decreases β-cell workload, hence the demand for insulin secretion, by: Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (β-cell workload) Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on β-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake Effect on Beta cell: Drucker DJ. Diabetes. 1998;47:159-169. Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand. 1997;160:413-422. Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997;160:413-422. Effects on Stomach: Nauck MA, et al. Diabetologia. 1996;39:1546-1553. Effects on CNS: Flint A, et al. J Clin Invest. 1998;101:515-520. Liver: ↓ Glucagon reduces hepatic glucose output Beta cells: Enhances glucose-dependent insulin secretion Stomach: Helps regulate gastric emptying Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.

The Incretin Effect Demonstrates the Response to Oral vs IV Glucose Oral Glucose IV Glucose 11 2.0 * 1.5 Incretin Effect DISCUSSION Despite the same plasma glucose profiles, there are significant differences in the -cell response to oral versus (vs) intravenous glucose, as measured by C-peptide. BACKGROUND This was a crossover study involving healthy subjects. Six young healthy subjects were given a 25, 50, or 100 g oral glucose load or isoglycaemic intravenous glucose infusions. The 50-g data is shown above. C-peptide may be a better measure of insulin secretion than plasma insulin, because C-peptide levels are not affected by hepatic insulin extraction. This difference in C-peptide levels in response to oral vs intravenous glucose suggests that other factors (incretins), and not merely the direct actions of plasma glucose, affect the insulin secretory response. 5.5 C-peptide (nmol/L) 1.0 Venous Plasma Glucose (mmol/L) 0.5 0.0 02 01 02 60 120 180 01 60 120 180 Time (min) Time (min) Mean ± SE; N = 6; *P .05; 01-02 = glucose infusion time. Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63:492-498. Copyright 1986, The Endocrine Society.

The Incretin Effect Is Reduced in Patients With Type 2 Diabetes Intravenous Glucose Oral Glucose Control Subjects Patients With Type 2 Diabetes 80 80 60 60 DISCUSSION The -cell secretory response to glucose ingestion, as measured by increases in plasma insulin, was reduced in patients with diabetes. Patients with diabetes exhibited a greater -cell secretory response than control subjects, as indicated by higher insulin secretion levels, during the 180-minute course of intravenous glucose infusion. BACKGROUND Differences in insulin response to oral and intravenous glucose administration, which are attributed to factors other than glucose itself, describe the incretin effect; the incretin effect appears to be reduced in patients with type 2 diabetes. measured insulin and C-peptide responses to a 50-g oral glucose load and an isoglycaemic intravenous infusion. Additionally, an attempt was made to correlate incretin effects to GIP responses. Insulin measurements are shown here. Plasma insulin responses were studied for 14 patients This study with type 2 diabetes and 8 metabolically healthy control subjects. Insulin (mU/L) 40 40 * * 20 20 30 60 90 120 150 180 30 60 90 120 150 180 Time (min) Time (min) *P ≤.05 compared with respective value after oral load. Nauck MA, et al. Diabetologia. 1986;29:46-52. Reprinted with permission from Springer-Verlag © 1986.