1. Part 6

2. The Quintessential Quintet
Islet b-cell
Impaired
Insulin Secretion
Decreased Incretin Effect
Increased
Lipolysis
The next factor to consider in type 2 diabetes pathophysiology is the decreased incretin effect, which can be observed in the glucose response of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in patients with IGT or type 2 diabetes.
This gives us the quintessential quintet.
Increased
HGP
Decreased Glucose
Uptake 2

3. GLP-1 and GIP Responses in Type 2 Diabetes
Postprandial GLP-1 Levels Are Decreased in Patients with IGT and T2DM
GIP Levels Are Increased in T2DM
NGT IGT T2DM * * 20 * *
P<0.01
100
Meal * * * *
An investigation of diminished incretin effect in type 2 diabetes analyzed postprandial GLP-1 concentrations (shown on the left) during a 4-hour mixed meal test in individuals with type 2 diabetes, IGT, or NGT.1
Compared with NGT subjects, those with type 2 diabetes had significant reductions (P<0.05) in postprandial GLP-1 levels.1
Further, after corrections for body mass index and gender, postprandial GLP-1 levels in patients with type 2 diabetes were also decreased relative to those with IGT.1
As shown on the right of the slide, another study of incretin hormones in type 2 diabetes found that GIP levels were significantly higher 30 to 90 minutes (P< ) after an OGTT in untreated patients with type 2 diabetes compared with healthy controls.2
Increased GIP levels in type 2 diabetes have been termed “GIP resistance.” However, as shown on the next slide, these findings have not been replicated, and the concept of GIP resistance remains under debate.
Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86:
Jones IR, Owens DR, Luzio S, Williams S, Hayes TM. The glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals is increased in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1989;32: * 80 15 * 60
GIP (pmol/L) 10
GLP-1 (pmol/L) * 40 5 20 60
120
180
240
-30 60
120
180
210
Time (min)
Time (min)
*P<0.05. GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
Jones IR, et al. Diabetologia. 1989;32: ; Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86: 3

4. GLP-1, GIP, and Insulin AUC Across the Spectrum of Glucose Tolerance4 16
P<0.005 12 14 3 10 12 8 2 10
In this study, investigators studied GLP-1, GIP, and insulin AUC following an OGTT in identical twins discordant for type 2 diabetes.
Significant decreases in insulin AUC were observed for twins with diabetes relative to their nondiabetic co-twins with NGT or IGT (P<0.0005) and relative to controls with NGT and no family history of diabetes (P< ).
GLP-1 AUC was significantly lower in subjects with diabetes than in healthy controls (P<0.05). No significant differences in GIP AUC were observed between twins with diabetes, their nondiabetic co-twins, or controls.
The finding that GIP levels remained unchanged in this study conflicts with the study shown on the previous slide. The impact of type 2 diabetes on GIP remains a subject of debate.
Vaag AA, Holst JJ, Vølund A, Beck-Nielsen HB. Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM)—evidence for decreased glucagon-like peptide 1 secretion during oral glucose ingestion in NIDDM twins. Eur J Endocrinol. 1996;135:
AUC1 GLP-1 (nmol/L · min) 6
AUC1 GIP (nmol/L · min) 8
AUC1 Insulin (mU/mL · min) 4 1 6 2 4 2 -2 -1
Controls
NGT
IGT
T2DM
Controls
NGT
IGT
T2DM
Controls
NGT
IGT
T2DM
Vaag AA, et al. Eur J Endocrinol. 1996;135:

5. Decreased Incretin Effect
The Setaceous Sextet
Islet b-cell
Impaired
Insulin Secretion
Decreased Incretin Effect
Islet a-cell
Increased
Glucagon Secretion
Next is the setaceous sextet, which takes into consideration the increased islet α-cell area and corresponding increased glucagon secretion and HGP in patients with type 2 diabetes.
Increased
Lipolysis
Increased
HGP
Decreased Glucose
Uptake 5

6. Pancreatic -Cells and -Cells in Normal Individuals
Endocrine mass
~50%
~35%
Role
Produce insulin and amylin
Produce glucagon
Mechanism of action
Secrete insulin in response to blood glucose elevations
Secrete glucagon in response to blood glucose decreases
Metabolic effect
Permit glucose uptake by peripheral tissues
Suppress glucagon and HGP
Stimulate HGP to meet energy needs between meals
The islets of Langerhans occupy approximately 1% to 5% of the total pancreatic mass in human adults. The islets include both pancreatic β- and α-cells.
β-Cells, which secrete insulin and amylin, comprise about 50% of the endocrine mass of the pancreas and reside in the central portion of the islet.
Residing in the periphery of the islets, α-cells comprise about 35% of the endocrine mass of the pancreas. These cells produce glucagon, which is released in response to low blood glucose levels.
Glucose homeostasis requires the integrated functioning of β- and α-cells. Insulin is a potent inhibitor of islet glucagon release; glucose indirectly suppresses glucagon secretion through increases in insulin.
Cabrera O, et al. PNAS. 2006;103: Cleaver O, et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21-39.
Cabrera O, et al. PNAS. 2006;103: ; Cleaver O, et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21-39.

7. Area of -Cells Is Increased in Type 2 Diabetes
-Cell Islet Area (%)
This slide shows α-cell mass as assessed from pancreatic postmortem analysis of subjects with type 2 diabetes (n=15) and age-matched controls (n=10).
Compared with control subjects, those with type 2 diabetes demonstrated a 58% increase in pancreatic α-cell islet area (P<0.05). The authors proposed that this increase might contribute to the hyperglucagonemia and hyperglycemia typical in type 2 diabetes.
Clark A, Wells CA, Buley ID, et al. Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res. 1988;9:
(n=10)
(n=15)
Clark A, et al. Diabetes Res. 1988;9:

8. Plasma Glucagon (pg/mL)
Basal Glucagon Levels and Basal Hepatic Glucose Production in Type 2 Diabetes
160
250
200
120
P<0.001
T2DM + SRIF
T2DM
+ SRIF
44%
58%
150
Basal HGP (mg/m2 • min)
This study of the role of glucagon in HGP involved 13 individuals with NGT and 10 with type 2 diabetes. Basal HGP was measured isotopically and was also studied during infusion of somatostatin (SRIF) in conjunction with glucose and insulin replacement, which isolated the effect of glucagon on HGP.
As shown on the right, glucagon levels were significantly higher in patients with type 2 diabetes versus control subjects (208±37 versus 104±15 pg/mL; P<0.001). As shown on the left, in the basal state, HGP was 66% greater among patients with type 2 diabetes (145 mg/m2 per min) than among control subjects (89 mg/m2 per min; P<0.01).
During SRIF, glucagon decreased by 44% in subjects with type 2 diabetes, to 119±26 pg/mL. This decrease corresponded with a 58% reduction in HGP among the diabetic patients, to 82 mg/m2 per min (P<0.001).
Baron AD, Schaeffer L, Shragg P, Kolterman OG. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes. 1987;36:
Plasma Glucagon (pg/mL) 80
100 40 50
NGT
T2DM
NGT
T2DM
SRIF=somatostatin infusion.
Baron A, et al. Diabetes. 1987;36: 8

9. Hyperglucagonemia and Insulin- Mediated Glucose Metabolism
Plasma Glucose (mmol/L)
Plasma Insulin (mU/L)
This slide illustrates the outcomes of a series of experiments designed to measure the effect of chronic hyperglucagonemia on HGP and insulin-mediated glucose action, as assessed in 14 young, healthy adult volunteers.
These figures show patients’ fasting concentrations of glucagon, plasma glucose, insulin, and FFAs at baseline and 24 and 48 hours following glucagon infusion and subsequent insulin clamp evaluation.
Following glucagon infusion, subjects experienced a stable ~50% increase in plasma glucagon concentration (from 242±14 pg/mL to 414±24 pg/mL). FPG concentrations showed an approximate 20% increase at both 24 and 48 hours (from 76±4 mg/dL [4.2±0.2 mmol/L] at baseline to 93±2 mg/dL [5.2±0.1 mmol/L] at 48 hours).
Fasting plasma insulin levels did not change substantially at either time point, while fasting FFAs showed progressive decline at both 24 and 48 hours (from 530±58 μmol/L at baseline to 410±47 and 354±33 μmol/L at 24 and 48 hours, respectively).
These results provided early evidence to suggest that diabetes is a bi-hormonal disease, with both insulin and glucagon levels contributing to the metabolic alterations observed in patients with diabetes.
Del Prato S, Castellino P, Simonson DC, DeFronzo RA. Hyperglucagonemia and insulin-mediated glucose metabolism. J Clin Invest. 1987;79:
Plasma Glucagon (mU/L) 24
48 hr
Plasma FFA (mol/l) 24
48 hr
Del Prato S, et al. J Clin Invest. 1987;79:

10. Peak Postprandial Plasma Glucose Level (mmol/L)
Inverse Relationship Between Insulin:Glucagon Ratio and Plasma Glucose in IGT
100
r=0.72
P<0.0001
r=-0.62
P<0.001 90 80 70
Glucose Appearance (mmol/5 hr)
This slide illustrates outcomes from a 1992 study designed to assess the specific contributions of insulin deficiency and insulin resistance in metabolic response. To control for the progressive damage caused by hyperglycemia in type 2 diabetes, this experiment was conducted among both normal individuals (n=16) and individuals with IGT (n=15); both groups included obese and nonobese individuals, matched for age and weight across cohorts.
Following glucose ingestion, subjects were evaluated for a number of physiologic parameters including peak postprandial glucose and plasma insulin and glucagon response.
As shown, both obese and nonobese subjects with IGT exhibited elevated postprandial glucose peaks in the context of a strong positive correlative relationship (r=0.72, P<0.0001). This observed difference was caused by IGT subjects’ reduced suppression of hepatic glucose.
Additionally, obese and nonobese subjects with IGT showed smaller reductions in plasma insulin-to-glucagon ratios, expressed as an inverse relationship (r=0.62, P<0.0001).
Mitrakou A, Kelley D, Mokan M, et al. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med. 1992;326:22-29. 60 50 40 6 8 10 12 14 5 10 15 20
Peak Postprandial Plasma
Glucose Level (mmol/L)
Plasma Insulin:Glucagon Ratio
Yellow symbols=NGT; green symbols=IGT; circles=nonobese; squares=obese.
Mitrakou A, et al. N Engl J Med. 1992;326:22-29.

11. Abnormal Meal-Related Insulin and Glucagon Dynamics in Type 2 Diabetes
360
Type 2 diabetes (n=12)
Normal subjects (n-=11)
330
Glucose (mg %)
300
270
240
110 80
120
This study of insulin, glucose, and glucagon dynamics involved patients with type 2 diabetes (n=12) versus nondiabetic control subjects (n=11).
After a large carbohydrate meal, mean plasma glucose increased dramatically by 125 mg/100 mL, from 228 mg/100 mL to 353 mg/100 mL in patients with type 2 diabetes. In contrast, glucose rose by only 53 mg/100 mL from the baseline value of 84 mg/100 mL in normal subjects.
In parallel, insulin rose sharply in the control subjects, from a mean fasting level of 13 µU/mL to a peak of 136 µU/mL within 45 minutes after the meal. In type 2 diabetes, however, the insulin response was delayed and suppressed, increasing from 21 µU/mL to only 50 µU/mL at 60 minutes.
In the control group, mean plasma glucagon levels declined significantly from the fasting value of 126 pg/mL to 90 pg/mL at 90 minutes (P<0.01). In contrast, among diabetic patients the mean plasma glucagon level rose slightly to 142 pg/mL at 60 minutes, before returning to the baseline value of 124 pg/mL at 180 minutes.
Müller WA, Faloona GR, Aguilar-Parada E, Unger RH. Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. N Engl J Med. 1970;283: 90
Insulin (µU/mL) 60
Delayed/depressed
insulin response 30
140
130
Nonsuppressed glucagon
120
Glucagon (pg/mL)
110
100 90
-60 60
120
180
240
Time (min)
Müller WA, et al. N Engl J Med. 1970;283:

12. Decreased Incretin Effect
The Septicidal Septet
Islet b-cell
Impaired
Insulin Secretion
Decreased Incretin Effect
Increased
Lipolysis
Islet a-cell
When increased glucose reabsorption is added to the mix of pathogenic factors, we are presented with the septicidal septet.
We will now look at the role of the kidneys in the pathogenesis of type 2 diabetes.
Increased Glucose
Reabsorption
Increased
Glucagon Secretion
Increased
HGP
Decreased Glucose
Uptake 12

13. Renal Glucose Reabsorption in Type 2 Diabetes
Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule
Renal glucose reabsorption is increased in type 2 diabetes
Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose
Inhibition of sodium-glucose cotransporter 2 (SGLT2) protein is a rational approach to therapy for type 2 diabetes for the reasons listed on this slide.
First, SGLT2 inhibitors reduce glucose reabsorption in the renal proximal tubule, resulting in glucosuria. This decreases plasma glucose levels and reverses glucotoxicity.
This approach to therapy is simple and nonspecific, and thereby would complement the action of all other antidiabetic agents, including insulin. As a result, even refractory type 2 diabetes will respond.
Wright EM, et al. J Intern Med. 2007;261:32-43. 13

14. Renal Handling of Glucose
(180 L/day) (900 mg/L)=162 g/day
Glucose
SGLT2 S1
The major role of the kidney in human physiology is to maintain intravascular volume and an acid-based electrolyte balance. Approximately 180 L of plasma per day pass through the kidney’s glomerular filtration system, wherein minerals such as sodium, potassium, and chloride are absorbed and returned to the bloodstream rather than passed out in the urine. Glucose is also filtered in this manner in order to retain energy essential for physiologic functioning between meals.1
With a daily glomerular filtration rate of 180 L, approximately 162 g of glucose must be reabsorbed each day to maintain a plasma glucose concentration of 5.6 mmol/L (101 mg/dL). As shown on the slide, reabsorption of glucose occurs mainly in the proximal tubule and is mediated by 2 different transport proteins, sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2). SGLT1, which occurs in the straight section of the tubule (S3), is responsible for approximately 10% of glucose reabsorption in the kidney. The other 90% is mediated by SGLT2, which occurs in the convoluted section on the tubule (S1).1
Although it varies from person to person, the maximal reabsorptive capacity of the proximal tubule averages 375 mg per minute. Because the filtered glucose load in healthy nondiabetic subjects is less than this, all filtered glucose is returned to circulation and none is excreted in the urine.2
Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. 2007;261:32-43.
Abdul-Ghani MA. Inhibition of renal glucose absorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14:
SGLT1 S3
90%
10%
No Glucose 14 14