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When you steal from one author, it's plagiarism; if you steal from many, it's research . Wilson Mizner. Normal Pancreatic Function. Exocrine pancreas aids digestion Bicarbonate Lipase Amylase Proteases Endocrine pancreas (islets of Langerhans) Beta cells secrete insulin

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When you steal from one author, it's plagiarism; if you steal from many, it's research

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When you steal from one author it s plagiarism if you steal from many it s research
When you steal from one author, it's plagiarism; if you steal from many, it's research

Wilson Mizner


Normal pancreatic function
Normal Pancreatic Function steal from many, it's research

  • Exocrine pancreas aids digestion

    • Bicarbonate

    • Lipase

    • Amylase

    • Proteases

  • Endocrine pancreas (islets of Langerhans)

    • Beta cells secrete insulin

    • Alpha cells secrete glucagon

    • Other hormones


Insulin stimulates cellular glucose uptake

Insulin steal from many, it's research

Insulin

Insulin

Insulin Stimulates Cellular Glucose Uptake

Adipocytes

Skeletal Muscle

Liver

Intestine & Pancreas


Type 1 diabetes hallmarks
Type 1 Diabetes: steal from many, it's research Hallmarks

  • Progressive destruction of beta cells

  • Decreased or no endogenous insulin secretion

  • Dependence on exogenous insulin for life


Absence of insulin
Absence of Insulin steal from many, it's research

  • Glucose cannot be utilized by cells

  • Glucose concentration in the blood rises

  • Blood glucose concentrations can exceed renal threshold

  • Glucose is excreted in urine


Presenting symptoms of type 1 diabetes
Presenting Symptoms of Type 1 Diabetes steal from many, it's research

  • Polyuria: Glucose excretion in urine increases urine volume

  • Polydipsia: Excessive urination leads to increased thirst

  • Hyperphagia: “Cellular starvation” increases appetite


Type 1 diabetes mellitus background
Type 1 Diabetes Mellitus: steal from many, it's research Background

  • Affects ~1 million people

  • Juvenile onset

  • Genetic component

  • Autoimmune/environmental etiology


Normal

Insulin steal from many, it's research

Glycerol

Lipolysis

Free fatty acids

Triglyceride

Synthesis

Free fatty acids

Glucose

LPL

Insulin

Normal


Type 1 diabetes mellitus

Triglyceride steal from many, it's research

LPL

Type 1 Diabetes Mellitus

Glycerol

Lipolysis

Free fatty acids

Synthesis

Free fatty acids

Glucose


Clinical chemistry

Normal steal from many, it's research

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

Clinical Chemistry


Insulin regulation of hepatic fatty acid partitioning
Insulin Regulation of Hepatic Fatty Acid Partitioning steal from many, it's research

FA-CoA

TG

ATP, CO2

-hydroxybutyrate

acetoacetate

Mitochondrion


In liver ffa entry into mitochondria is regulated by insulin glucacon
In Liver: steal from many, it's research 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


Malonyl coa is a regulatory molecule
Malonyl CoA is a Regulatory Molecule steal from many, it's research

  • 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


Ketone bodies
Ketone Bodies steal from many, it's research

  • Hydroxybutyrate, acetoacetate

  • Fuel for brain

  • Excreted in urine

  • At 12-14 mM reduce pH of blood

  • Can cause coma (diabetic ketoacidosis)


Natural history of pre type 1 diabetes
Natural History Of “Pre”–Type 1 Diabetes steal from many, it's research

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)

Genetic

predisposition

Insulitis-Cell injury

“Pre”-diabetes

Diabetes

Time

Eisenbarth GS. N Engl J Med. 1986;314:1360-1368

14


When you steal from one author its plagiarism if you steal from many its research

Case 1 steal from many, it's research 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%.


The miracle of insulin
The Miracle of Insulin steal from many, it's research

February 15, 1923

Patient J.L., December 15, 1922


Primary defect in type 2
Primary Defect in Type 2 steal from many, it's research

  • 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


Why is glucose transport reduced
Why is Glucose Transport Reduced? steal from many, it's research

  • Mitochondrial phosphorylation decreased 30%

  • Intramyocellular lipid is increased 80%

  • Ectopic fat may hinder insulin-stimulation of glucose transport.


What is consequence of muscle insulin resistance
What is consequence of muscle insulin resistance? steal from many, it's research

  • Pancreas compensates > hyperinsulinemia

  • Hyperinsulinemia exacerbates insulin resistance in adipose tissue.


Consequences of insulin resistance in adipose tissue
Consequences of Insulin Resistance in Adipose Tissue steal from many, it's research

  • Similar to insulin deficiency

  • Reduced TG synthesis

  • Enhanced lipolysis

  • Net increase in FA availability to non-adipose tissues


Consequences of insulin resistance ffa in muscle
Consequences of Insulin Resistance steal from many, it's research FFA in Muscle

  • Increased intramyocellular lipid

  • Hypothetical: inhibition of insulin signaling by diglyceride

  • Reduction in glucose uptake by muscle


Consequences of insulin resistance ffa in liver
Consequences of Insulin Resistance steal from many, it's research FFA in Liver

  • Increased triglyceride synthesis

  • Increased oxidation

  • Increased gluconeogenesis

  • Hepatic glucose output contributes to hyperglycemia


Consequences of insulin resistance ffa in pancreas
Consequences of Insulin Resistance steal from many, it's research FFA in Pancreas

  • Animal models of diabetes

  • Lipid droplets accumulate in beta cells

  • Beta cells undergo apoptosis

  • Reduced beta cell mass

  • Decreased circulating insulin


When you steal from one author its plagiarism if you steal from many its research

KEY POINTS steal from many, it's research

■ 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


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