Insulin Secretion, Beta Cell Biology

Insulin Secretion, Beta Cell Biology and the Pathogenesis of Type 2 Diabetes


Kenneth S. Polonsky
Presentation by:Professor of Medicine, Cell Biology and Physiology
Director Institute of Clinical and Translational Sciences
Washington University School of Medicine

Diabetes:Basic Abnormalities
Islets of Langerhans
GLUCOSE
Pancreas
Muscle
Liver
Fat

INSULIN
* The pancreas does not produce enough insulin
* Muscle, liver and fat tissues don’t respond to insulin-insulin resistance
* Elevated Fatty Acids impair insulin secretion and action

Normal Glucose Tolerance
Genetic susceptibility
Diabetogenic Lifestyle
Normal Glucose Tolerance
Insulin Resistance
Compensatory hypersecretion of insulin
Impaired Glucose Tolerance
Insulin Resistance
β-cell compensation starts to fail
Overt Hyperglycemia
Insulin Resistance
Failed β-cell compensation

Pancreatic beta-cell dysfunction in overt type 2 diabetes
* Abnormal insulin secretion
o Absent first phase response to intravenous glucose
o Delayed and blunted response to a mixed meal
o Abnormal insulin secretory oscillations
o Increased levels of proinsulin and proinsulin breakdown intermediates
* Reduced beta cell mass

Glucose infusion rate (mg/kg/min)
Resistant

Intravenous Glucose Infusion in Insulin resistant subjects
Insulin Secretion and Glucose
Lean Control
Failure of insulin secretion to respond to glucose oscillations in IGT
Decreased Insulin Content in Type 2 Diabetes
T2DM=Type 2 diabetes.
Decrease in Beta-Cell Volume in Type 2 Diabetes
Obese
Lean
Conclusions

* Progressive abnormalities in insulin secretion are consistently present as people progress from NGT to IGT to Diabetes.
* Increases in glucose concentrations within the normal range are associated with progressive reductions in insulin secretion.
* Insulin resistance is consistently present along with defects in insulin secretion and results cannot resolve which factor is playing a primary role.

Classification Based on Genetic Mechanism and Age of Clinical Presentation
Monogenic
* Neonatal diabetes
* Diabetes in older children and young adults (MODY)
* Mitochondrial diabetes
Polygenic
* Type 2 Diabetes in adults
Genome Wide Association Studies
Recent Smaller Genome Wide Association Studies
Transcription factor in Wnt pathway
Polygenic type 2 diabetes genes
Mechanism-Beta cell
Genes that cause or are associated with diabetes
Overall summary and conclusions
* Genetic variation at multiple loci contribute to overall diabetes risk and to date account for <5% of diabetes genetic risk.
* The genes identified affect insulin secretion predominantly.
* Insulin secretion is abnormal at all stages in the evolution of type 2 diabetes and in genetically predisposed individuals with normal glucose.
* The complexity of these results have raised questions regarding the feasibility of personalized medicine and at this stage it is not clear if genetic testing will add to clinical management of the majority of diabetic patients.

Glucose Metabolism
* Glucokinase
* Hnf1α
Glucokinase
* The enzyme that phosphorylates glucose to glucose-6-phosphate allowing further metabolism in the glycolytic pathway
* Expressed in the pancreatic beta cell and liver
* Based on knowledge of physiology, mutations would be predicted to cause
o hyperglycemia associated with
o reduced glucose induced insulin secretion
o reduced liver glycogen

Relationship between Glucose and Insulin Secretion Rate
Changes in Hepatic Glycogen content after meals
Effects of mutations that activate or impair glucokinase activity
Summary
* Subjects with E23K polymorphisms in Kir6.2 who have normal blood glucose levels have reduced insulin secretion.
* At this stage insulin sensitivity is enhanced when compared to matched controls.
* This could be a compensatory response to reduced insulin secretion or an effect of the polymorphism on insulin action.
Beta cell survival and mass
Observations from islet isolation
Questions
Decrease in Beta-Cell Volume in Type 2 Diabetes1

Insulin Secretion.ppt

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MATURITY-ONSET DIABETES OF THE YOUNG

MATURITY-ONSET DIABETES OF THE YOUNG
Presentation by:Stefan S. Fajans, MD
University of Michigan

Definition
* Type-2 diabetes mellitus in the young plus
* Autosomal dominant inheritance

Current Definition of MODY
* A heterogeneous disorder due to heterozygous monogenic mutations in one of at least 6 different genes
* Onset of diabetes early in life: childhood, adolescence, young adulthood
* Autosomal dominant inheritance
* Primary defect in insulin secretion

Heterozygous Gene Mutations Identified in MODY
Homozygous Mutations of MODY-Related Genes
MODY-Related Proteins
Distinguishing Clinical Characteristics of MODY and Type 2 Diabetes (DM2)
MODY1 (HNF-4a Mutation):
Tested and normal
Type 1 diabetes
PVD-A-G
Multiple offspring
MODY1 (HNF-4a Mutation):
Tested and normal
Type 2 diabetes
Phenotypic Expression and Natural History of MODY
MODY1 (HNF-4a Mutation):
Protocol for the Stepped Glucose Infusion Method to Determine Insulin Secretion Rate

MATURITY-ONSET DIABETES OF THE YOUNG.ppt

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Overview of carbohydrate metabolism

Overview of carbohydrate metabolism
Presentation by: Dr. Nuran Ercal

GLYCOLYSIS
* Glycolysis occurs in almost every living cell.
* It occurs in cytosol.
* It was the first metabolic sequence to be studied.
* Most of the work done in 1930s by the German biochemist G. Embden Meyerhof Warburg.
* That is why it is also called Embden-Meyerhof pathway.
* It is a greek word.
* Glykos------> sweet
* Lysis-------> loosing
* Glycolysis-----------> loosing or splitting of glucose
* Glc is an important fuel for most organisms.
* Why is Glc chosen?
* 1) Glc is one of the monosaccarides formed formaldehyde
* under prebiotic conditions.
* 2) Glc has a low tendency to glycosylate proteins
* Fermentations provide usable energy in the absence of oxygen
* Why is a relatively inefficient metabolic pathway so extensively
* used?
* Answer: It does not require oxygen
* Obligate anaerobes
* Facultative anaerobes
* 3 of the reactions of glycolysis are irreversible.
* Pyruvate is the end product of glycolysis in tissues with mitochondria.
* This series of 10 reactions called aerobic glycolysis,

Stages of glycolysis
* Stage I
* Goal: To trap the Glc in the cell

IMPORTANCE OF PHOSPHARYLATED INTERMEDIATES
PHOSPHORYLATION OF GLUCOSE
Induced fit in Hexokinase
Difference between hexokinase and glucokinase
Hexokinase vs glucokinase
SUMMARY
More about HK
* Hexokinase, like adenylate kinase and all other kinases, requires Mg (or Mn) for activity.
* Hexokinase is also one of the induced-fit model enzymes.
* It has two lobes that move towards each other when Glc is bound!
* Substrate-induced cleft closing is a general feature of kinases.
* Other kinases (Pyruvate kinase, phosphoglycerate kinase and PFK) also contain clefts between lobes that close when substrate is bound.

2. ISOMERIZATION OF G-6-P
3. PHOSPHORYLATION OF F-6-P
4. CLEAVAGE OF F-1,6BIP
5. ISOMERIZATION OF DIHYDROXYACETONE-P
6. OXIDATION OF GLYCERALDEHYDE 3-P.
Structure of glyceraldehyde 3-phosphate dehydrogenase
7: FORMATION OF ATP FROM 1,3-BIPGLYCERATE AND ADP
Q:Why does PEP have such a high P-ryl potential?
Pyruvate kinase deficiency:
Maintaining redox balances

Overview of carbohydrate metabolism.ppt

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