1. In T2DM, β-Cell Mass in Islets is Significantly Reduced
Control
T2DM
35% -cells
65% β-cells
52% -cells
48% β-cells
P <0.01
Adapted from Deng S, et al. Diabetes. 2004;53:

2. So ‘maybe’ Insulin need in T2DM overstated 
Phenotypic Presentation is defined by:
Slope = ‘Natural History’ over time,i.e.,RATE OF β-cell LOSS. Slope is not linear in either T1DM or T2DM, and may be intermittently relapsing, remitting, stabilized, and improved. Complete loss of β-cell mass may never be reached, especially if newer agents better preserve β-cells.
100% −
0% −
Severity =
β-cell loss of mass
Beta cell mass is a function of relative rates of apoptosis, replication and neogenesis
Pre-Diabetes = FBS ≥100, PPG ≥140
All DM = FBS ≥126, PPG ≥200
Critical
β−Cell
Mass %
β−Cell
Mass
Disease Modification
I I I I I/ ≈ / I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I
Increasing Age
Age at presentation = tipping point when the combined gene effect / environmental trigger is exposed as phenotypic hyperglycemia

3. DURABILITY OF GLYCEMIC CONTROL WITH SULFONYLUREAS1
Glyburide
Glyburide
Glimepiride SU
Glyburide
GLY
Alvarsson (n=39) SU
Alvarsson (n=48)
Gliclazide
RECORD (n=272)
Change in HbA1c (%)
Glyburide
Hanefeld (n=250)
Charbonnel (n=313) -1
Gliclazide
UKPDS (n=1,573)
Chicago (n=230)
ADOPT (n=1,441)
PERISCOPE (n=181)
Tan (n=297) -2 1 2 3 4 5 6 10
TIME (years) 3

4. a Myth Natural History- Usual ‘Story’- Progressive Loss of Mass
Requiring Insulin Therapy in Many/Most-
a Myth
1. Progressive Decline in Function – multiple causes of b-cell damage-
decreased function>mass- worse with with SU/ Insulin TX
BUT
2. Med School- need to do 80% pancreatectomy to become diabetic
3. “..no more than 20-25% of pancreas needed to stay normal after distal pancreatectomy (King-from ref. below )
4. After Bariatric surgery- even 20 years DM, 15 on insulin-
3 days later no need for insulin,
Or , often, on no anti-dm medicine at all
So.. Have more b-cells after years than most believe
So.. No Sulfonylurea- destroys b-cells;
Delay Insulin- avoid effects of hyperinsulinism- hypo- wt.gain
Use agents that preserve B-cell function (DeFronzo’s Triple Therapy) -and may decrease CV outcomes
So.. No need for early insulin
If need insulin- one can avoid bolus in most !! .
J Gastrointest Surg (2008) 12:1548–1553,Distal Pancreatectomy: Incidence of Postoperative Diabetes
Jonathan King & Kevork Kazanjian & J. Matsumoto & Howard A. Reber & Michael W. Yeh & O. Joe Hines & Guido Eibl

5. Exquisitely controlled levels of insulin released into the portal vein
NOTE: There is NO perfect Exogenous Insulin: All result in HyperInsulinemia and Potential Hypoglycemia
Exquisitely controlled levels of insulin released into the portal vein
Fine-tuned, physiologically appropriate insulinemia
Endogenous Insulin
‘Obligatory’ excess peripheral insulin to get modicum of reduced hepatic glucose production
Exogenous Insulin
Insulin Resistance
β-cell Dysfunction
Potential
β-cell Exhaustion
Hypoglycemia
Obesity
Hyperinsulin-emia
Atherosclerosis
All because all insulin results in hyperinsulinemia with risk of negative consequences
Weight gain
Hypertension
Dyslipidemia
Cancer
Chronic Inflammation
Type II Diabetes

6. Avoid Early Insulin Therapy (except in Ketosis-prone) Vicious Circle(s) of Hyperinsulinemia- Result in Weight Gain and Hypoglycemia
Blood glucose rises
Undue Basal
Or bolus Insulin
=Overinsulinized
Patient eats too much
Or simple sugars
Hypoglycemia
Symptomatic or not!
INCREASED APPETITE

7. ORIGIN TRIAL With Early Insulin Therapy No Benefit in reducing Adverse CV Outcomes and increased hypoglycemia and wt. gain

8. Increased Mortality, MACE, Cancer 1-year After Starting insulin- 2014
Diabetes Obes Metab. 2014 Nov 14. doi: /dom [Epub ahead of print]
Glucose-lowering with exogenous insulin monotherapy in type 2 diabetes: dose association
 with all-causemortality, cardiovascular events and cancer.
Holden SE1, Jenkins-Jones S, Morgan CL, Schernthaner G, Currie CJ.

10. Value to Early Insulin Therapy- Outweighed By Hypoglycemia Weight Gain ….