1. When you steal from one author, it's plagiarism; if you steal from many, it's research
Wilson Mizner

2. Normal Pancreatic Function
Exocrine pancreas aids digestion
Bicarbonate
Lipase
Amylase
Proteases
Endocrine pancreas (islets of Langerhans)
Beta cells secrete insulin
Alpha cells secrete glucagon
Other hormones

3. Insulin Stimulates Cellular Glucose Uptake
Adipocytes
Skeletal Muscle
Liver
Insulin
Intestine & Pancreas

4. Insulin actions in peripheral tissues
Insulin actions in peripheral tissues. Protein phosphorylation is required to mediate insulin action. After receptor autophosphorylation, the ß subunit becomes active as a tyrosine-specific kinase and catalyzes phosphorylation of several intracellular proteins. This event promotes the multifaceted actions of insulin. Insulin stimulates glucose turnover by favoring its transport across the plasma membrane followed either by oxidative or nonoxidative disposal, the latter being associated with glycogen synthesis. The effect of insulin on glucose transport is observed only in skeletal muscle, adipose cells, and heart. Insulin promotes protein synthesis in almost all tissues by virtue of a combined effect on gene transcription, messenger RNA translation, and amino acid uptake. Insulin also has a mitogenic effect that is mediated through increased DNA synthesis and prevention of programmed cell death, or apoptosis. In addition, insulin stimulates ion transport across the plasma membrane of multiple tissues. Finally, insulin stimulates lipid synthesis in fat cells, skeletal muscle, and liver while preventing lipolysis by inhibiting hormone-sensitive lipase. There is increasing evidence for a direct role of insulin, acting through the insulin or insulin-like growth factor (IGF) receptors, to regulate pancreatic ß-cell growth, survival, and insulin release from the pancreatic ß cells [],[]. Different tissues are known to respond differently to insulin. While tissue sensitivity to insulin correlates with the levels of insulin receptors expressed on the plasma membrane, it is clear that the assembly of different components of the insulin signaling pathway also confers specificity of insulin signaling on target cells. Thus, insulin-dependent glucose transport is only observed in skeletal muscle and adipose cells because these cells possess the insulin-dependent glucose transporter GLUT4. Likewise, the effect of insulin to inhibit gluconeo-genesis is specific to liver and kidney. In contrast, the effects on gene expression and protein synthesis might be ubiquitous.

8. Type 1 Diabetes: Hallmarks
Progressive destruction of beta cells
Decreased or no endogenous insulin secretion
Dependence on exogenous insulin for life

9. Absence of Insulin Glucose cannot be utilized by cells
Glucose concentration in the blood rises
Blood glucose concentrations can exceed renal threshold
Glucose is excreted in urine

10. Presenting Symptoms of Type 1 Diabetes
Polyuria: Glucose excretion in urine increases urine volume
Polydipsia: Excessive urination leads to increased thirst
Hyperphagia: “Cellular starvation” increases appetite

11. Type 1 Diabetes Mellitus: Background
Affects ~1 million people
Juvenile onset
Genetic component
Autoimmune/environmental etiology

12. Normal Insulin Glycerol Lipolysis Free fatty acids Triglyceride
LPL
Triglyceride
Lipolysis
Glycerol
Free fatty acids
Free fatty acids
Glucose
Synthesis
Insulin

13. Type 1 Diabetes Mellitus
Triglyceride
LPL
Glycerol
Lipolysis
Free fatty acids
Synthesis
Free fatty acids
Glucose

14. Clinical Chemistry Normal Uncontrolled Type 1
Fasting blood glucose < 100 mg/dL
Serum free fatty acids
~ 0.30 mM
Serum triglyceride ~100 mg/dL
Uncontrolled Type 1
Fasting blood glucose up to 500 mg/dL
Serum free fatty acids
up to 2 mM
Serum triglyceride
> 1000 mg/dL

15. Insulin Regulation of Hepatic Fatty Acid Partitioning
FA-CoA TG
ATP, CO2
-hydroxybutyrate
acetoacetate
Mitochondrion

16. In Liver: FFA Entry into Mitochondria is Regulated by Insulin/Glucacon
Malonyl CoA
carnitine
carnitine
FA-CoA
CPT-II
FA-CoA
CPT-I
ATP, CO2
HB, AcAc
inner
outer TG
Mitochondrial
membranes
CPT= Carnitine Palmitoyl
Transferase

17. Malonyl CoA is a Regulatory Molecule
Condensation of CO2 with acetyl CoA forms malonyl CoA
First step in fatty acid synthesis
Catalyzed by acetyl CoA carboxylase
Enzyme activity increased by insulin

18. Ketone Bodies Hydroxybutyrate, acetoacetate Fuel for brain
Excreted in urine
At mM reduce pH of blood
Can cause coma (diabetic ketoacidosis)

19. Natural History Of “Pre”–Type 1 Diabetes
Putative
trigger
-Cell mass 100%
Cellular autoimmunity
Circulating autoantibodies (ICA, GAD65)
Loss of first-phase
insulin response (IVGTT)
Clinical
onset—
only 10% of -cells remain
Glucose intolerance
(OGTT)
History of “Pre”–Type 1 Diabetes
KEY POINTS
• The natural history of type 1 diabetes is marked by a progressive
destruction of the â-cells by an autoimmune process
• The process begins with genetic susceptibility and may involve environmental
triggers, leading to â-cell injury
• Autoantibodies may be detected up to a decade before overt type 1
diabetes develops
• Pre–type 1 diabetes is marked by a progressive loss of glucose-stimulated
insulin secretion and the loss of the first-phase insulin
response
• With the clinical onset of type 1 diabetes and overt hyperglycemia,
only about 10% of â-cells remain
• Several years after the development of overt diabetes, â-cell destruction
is complete
This slide illustrates the natural history of type 1 diabetes, which is characterized
by the gradual autoimmune destruction of the pancreatic â-
cells. The process begins with genetic susceptibility. All humans have at
least one gene in the major histocompatibility region that contributes to
susceptibility to diabetes. However, the inheritance of diabetes is multigenic
and involves one or more genes outside the major histocompatibility
complex.1,2
In some individuals, a triggering event that injures the â-cell may occur,
such as exposure to certain drugs, infectious agents, or viruses.
Congenital rubella infection, for example, is a well-recognized environmental
trigger for type 1 diabetes. Active autoimmunity develops with
detectable levels of circulating autoantibodies, including islet cell antibodies
(ICA) and glutamic acid decarboxylase (GAD) antibodies. However, the
presence of autoantibodies can precede the development of overt type 1
diabetes by over 10 years.1,2
During the next, prediabetes stage, glucose-stimulated insulin secretion
progressively declines, as evidenced by the loss of first-phase insulin
secretion in response to intravenous glucose challenge and glucose
intolerance following OGTT.1
With the clinical onset of type 1 diabetes (overt hyperglycemia), extensive
â-cell destruction has occurred and only about 10% of â-cells
remain. Several years after the development of overt diabetes, â-cell
Genetic
predisposition
Insulitis -Cell injury
“Pre”-diabetes
Diabetes
Time
Eisenbarth GS. N Engl J Med. 1986;314: 14

20. Case 1 R.T., a 15-year-old male with type 1 diabetes presented with a 5-day history of nausea and vomiting. He also reported a 2-week history of polyuria and polydipsia and a 10-lb weight loss.
The patient was diagnosed with type 1 diabetes 2 years ago when he presented to a different hospital with symptoms of polyuria, polydipsia, and weight loss.
The laboratory data showed an anion gap, metabolic acidosis, and hyperglycemia (pH of 7.14, anion gap of 24, bicarbonate 6 mmol/l, urinary ketones 150 mg/dl, glucose 314 mg/dl) consistent with the diagnosis of DKA. The patient's hemoglobin A1c (A1C) was 13.5%.

21. The Miracle of Insulin Patient J.L., December 15, 1922
February 15, 1923

24. Primary Defect in Type 2
Study healthy 1st degree relatives of patients with type 2
Measure ability of body to use glucose
Find defects in muscle glucose uptake before any symptoms develop

25. Why is Glucose Transport Reduced?
Mitochondrial phosphorylation decreased 30%
Intramyocellular lipid is increased 80%
Ectopic fat may hinder insulin-stimulation of glucose transport.

26. What is consequence of muscle insulin resistance?
Pancreas compensates > hyperinsulinemia
Hyperinsulinemia exacerbates insulin resistance in adipose tissue.

27. Consequences of Insulin Resistance in Adipose Tissue
Similar to insulin deficiency
Reduced TG synthesis
Enhanced lipolysis
Net increase in FA availability to non-adipose tissues

28. Consequences of Insulin Resistance FFA in Muscle
Increased intramyocellular lipid
Hypothetical: inhibition of insulin signaling by diglyceride
Reduction in glucose uptake by muscle

29. Consequences of Insulin Resistance FFA in Liver
Increased triglyceride synthesis
Increased oxidation
Increased gluconeogenesis
Hepatic glucose output contributes to hyperglycemia

30. Consequences of Insulin Resistance FFA in Pancreas
Animal models of diabetes
Lipid droplets accumulate in beta cells
Beta cells undergo apoptosis
Reduced beta cell mass
Decreased circulating insulin

34. KEY POINTS
■ Resistance to the actions of insulin is strongly associated with the microvascular complications of diabetes, independently of metabolic control and hypertension
■ Insulin resistance is an important marker of risk and a key target for intervention, as those patients who achieve a greater improvement of insulin sensitivity achieve better microvascular outcomes
■ Diabetes and obesity are associated with pathway-selective insulin resistance in the phosphatidylinositol-3-kinase signaling pathway, while signaling via extracellular signal-regulated kinase dependent pathways is comparatively unaffected, tipping the balance of insulin’s actions in favor of abnormal vasoreactivity, angiogenesis, and other pathways implicated in microangiopathy
■ Insulin resistance is able to enhance key pathways involved in hyperglycemia-induced microvascular damage and to exacerbate hypertension
■ The strong association between insulin resistance and microvascular disease might also reflect a common genotype or phenotype