glucagon and diabetes mellitus

what does an increase in insulin allow

allows delivery of glucose from blood to tissues

what are the 2 types of diabetes

• primary diabetes

• secondary diabetes

what are the 2 types of primary diabetes

• type 1

• type 2

what was type 1 diabetes formally known as

insulin-dependent diabetes mellitus

what was type 2 diabetes formally known as

non-insulin-dependent mellitus

how many cases of diabetes are secondary diabetes

1-2%

what is secondary diabetes commonly due to

• liver disease (cirrhosis)

• pancreatic disease (cystic fibrosis)

• endocrine disease (Cushing’s syndrome)

how can secondary diabetes be induced

can be drug induced

what is cirrhosis

chronic scarring of the liver

what is gestational diabetes

diabetes during pregnancy (usually in second or third trimester)

how many cases of gestational diabetes are there

occurs in 3-4% of all pregnancies

what is gestational diabetes caused by

• insulin resistance

• more to do with how insulin works at the receptors

how can gestational diabetes be managed

• usually by diet

• may need to be prescribed insulin

what is the risk of gestational diabetes

risk of large birth weight baby

what happens to most cases in gestational diabetes after a patient has given birth

patient returns to normal blood glucose levels and insulin sensitivity following delivery

what does the term epidemiology mean

the study of how often diseases occur in different groups of people and why

how many adults worldwide live with diabetes

537 million

how many deaths are there worldwide due to diabetes

6.7 million 

how many people in the UK are diagnosed with diabetes

4.4 million

what is the estimation on the amount of people in the uk who are undiagnosed for diabetes

1.2 million

what is the percentage of people who have type 1 or type 2 diabetes in the uk

• 90% are type 2

• 8% type 1

• 2% rarer forms

what does the term aetiology mean 

why does this occur

when is type 1 diabetes present

• present at any age

• prominent disease of childhood

• peaking at puberty

what is the presence of type 1 diabetes in people <20 years of age

50-60% present

what type of disease is type 1 diabetes

• HLA-associated immune-mediated disease

• >90% carry HLA-DR3 and/or DR4

• more pre-disposed to type 1 disease

is type 1 diabetes genetically pre-determined

• no 

• but increased susceptibility to disease may be inherited 

what is the percentage of islet cell antibodies in type 1 diabetes at the point of diagnosis

• >70%

• appear in circulation several years before clinical presentation

are there any environmental effects type 1 diabetes 

• yes

• triggers a cascade of events for the auto-immune disease

which type of primary diabetes has a stronger genetic relationship

type 2

what is a risk-factor for developing type 2

• obesity 

• occurs in 80% cases 

what happens in type 2 diabetes to insulin

• increased insulin resistance 

• decreased number of beta-cells 

what happens to someone at birth with someone with type 2 diabetes

• low birth weight and weight at 12 months 

• poor nutrition in early life 

• impaired beta-cell development and function

what does metabolic syndrome lead to

endothelial cell dysfunction (atherosclerosis)

what are the effects when there is a combination of medical disorders when occurring together

• increased blood pressure

• increased blood glucose 

• central abdominal obesity 

• increased cholesterol 

what is the pathophysiology of diabetes that causes hyperglycaemia 

• decreased mass of pancreatic beta-cells 

• down regulation of insulin receptors 

• unregulated hepatic glycogenolysis and gluconeogenesis 

what is the percentage pancreatic beta-cells in type 1 and type 2 diabetes 

• type 1: <5-10% remaining 

• type 2: 50% remaining 

what is the pathophysiology of diabetic ketoacidoses

• metabolic disturbance + / - acute illness e.g. infection 

• increased counter-regulatory hormones

• further increased hepatitis glucose production

• increased lipolysis

• uptake to liver to produce acetylcholine CoA

• metabolism exceeded

• ketone bodies

what are the common symptoms for both types of primary diabetes

• polyuria- due to osmotic diuresis when blood glucose exceeds renal threshold

• polydipsia- thirst- due to resulting fluid and electrolyte loss

• weight loss- due to fluid depletion and increased breakdown of fat and muscle 

• blurred vision- due to glucose induced changes in refraction 

what are the clinical manifestations of type 1 diabetes

• diabetic ketoacidosis

• increased blood glucose - osmotic diuresis and dehydration

• increased ketone bodies- metabolic acidosis 

• hyperosmolality

• potassium loss

• muscle catabolism 

what are some symptoms of diabetic ketoacidosis

• hyperventilation

• nausea and vomiting

• dehydration

• weakness

• ketone breath

• reduced consciousness

• potentially fatal

clinical manifestations of type 2 diabetes

• often insidious onset with few or none of the classical symptoms

• may only be detected as part of routine investigation 

• chronic skin infections

• pruritic and candida infection of the vagina 

• can present first as the complications- retinopathy, neuropathy, foot ulcers, nephropathy

what is another clinical manifestation of type 2 diabetes

• hyperosmolar hyperglycaemic state (HHS)

what is HHS similar to 

• diabetic ketoacidosis

• no significant ketosis and no acidosis due to endogenous insulin levels being sufficient to inhibit hepatic ketogenesis, but hepatic glycogenolysos and gluconeogenesis still occur 

what is the range of normal blood glucose levels 

3.4-5.8 mmol/l

if a patient has symptoms of diabetes what will their random venous plasma glucose ;levels look like

greater than or equal to 11.1 mmol/l

if a patient has symptoms of diabetes what will their fasting venous plasma glucose levels look like

greater than or equal to 7.0 mmol/l

when Is a oral glucose tolerance test used 

used for borderline cases and diagnosis of gestational diabetes 

if a patient has symptoms of diabetes what will the plasma glucose levels be 2 hrs after 75g anhydrous glucose in an oral glucose tolerance test

greater than or equal to 11.1 mmol/l

if a patient has no symptoms of diabetes how many measurements should be taken

at least 2 separate measurements

what can complications of diabetes mellitus be divided into

• caused by micro-vascular disease

• secondary to macro-vascular disease

what are the different complications of diabetes caused by micro-vascular disease

• eyes- retinopathy

• kidneys- nephropathy

• nerves- neuropathy

what are the different complications of diabetes secondary to macro-vascular disease

• blood pressure- hypertension

• blood lipids- hyper-lipidaemia 

why are the eyes, kidneys and nerves vulnerable to damage

because the endothelial cells of the retina, kidney, and peripheral nervous system allow glucose to enter the cells even in the absence of insulin

what is diplopia

double vision

when does diabetic retinopathy usually occur

• within 20 years of diagnosis of diabetes

what does diabetic retinopathy start with

starts with small haemorrhages and abnormal spots of hardened exudates (leaked fluids)

what does diabetic retinopathy progress into

infarction of the retina- areas with little or no blood supply

what is different to the new blood vesseles as a result of diabetic retinopathy 

• they are fragile

• tend bleed and destroy the retina unless they are treated early enough 

what is the treatment for diabetic retinopathy

• laser treatment to seal off the leaking blood vessels 

• prevent development or progression by maintaining good glycemic control, manage hypertension and avoid smoking

what os diabetic nephropathy the leading cause of 

• end-stage renal failure

• responsible for more than 1/3 patients on dialysis

what causes diabetic nephropathy

• hypertension and hyperglycaemia-induced changes to the glomerular cells in the kidney and mesangial cells

• increased pro-inflammatory mediators 

common signs of diabetic nephropathy

• proteinuria- protein in urine

• microalbuminuriaa (result of hyper filtration and hyper perfusion)

what is the treatment for diabetic nephropathy

• control diabetes, blood pressure and other risk factors 

what can diabetic neuropathy cause

• numbness occurs in both legs, sometimes pain, tingling and itching may also be present 

• impaired sense of position leading to the patient being unsteady on their feet and decreased vibration sense

motor neuropathy

• neuropathy of autonomic nerves leading to erectile dysfunction in men, orthostatic hypotension, delayed emptying of the stomach

treatment for diabetic neuropathy

• pain modifying agents (paracetamol)

• analgesics for pain (carbamazepine)

how many diabetics get diabetic foot

• 15% will get a foot ulcer at some point in their life

• of these 5-15% eventually require amputation

what is diabetic foot a result of

• peripheral vascular disease

• poor circulation

• ischaemia of lower limbs 

• reduced infection healing and difficulty getting antibiotics to wound area

how many deaths does CVD account for in diabetics

60%

how much higher is the risk of CVD in diabetics compared to non-diabetics

2-4x higher

what are high risk patients of CVD prescribed

• statins 

• statins may also be given to patients aged 18-39 id they have diabetic complications

how to reduce risks of CVD

• healthy diet and lifestyle 

• good blood glucose control 

• annual check of blood lipids

• weight reduction

aims of therapy for diabetes

• treat hyperglycaemia without causing hypoglycaemia 

• reduce risk of long term complications

• enable patient to maintain a normal lifestyle whilst ensuring adequate diabetic control 

what are some ways to treat diabetes

• healthy lifestyle and optimum weight

• drugs ti increase insulin function (type II) and manage complications

• insulin injection (Type I)

how many types of insulin injections are there

5

what are the 5 different types of insulin

• rapid acting analogues

• short acting

• medium and loner acting

• analogue mixture

• mixtures

rapid acting analogues

• novorapid, Humalog

• injected 5-15 mins before eating, when eating to immediately after eating and lasts between 2-5 hr in body 

• often taken in combination with longer acting insulin 

short acting

• acrarapid, humalin S

• injected 15-30 mins before a meal and can work for up to 8hr in body

• often used in combination with longer-acting insulin

medium and longer acting insulin

• insulatard, humulin I

• last up to 24 hr 

• injected at night

analogue mixtures

• novomix 30, Humalog mix

• last approx. 14-16 hrs

• injected 5-15 mins before food intake 

mixtures

• humulin M3, insuman comb

• last approx. 12 hours

• injected 20-30 mins before food intake 

what are the different routes insulin is administered by injection

• vial and syringe

• disposable or re-usable pen and cartridge 

• insulin pump 

why is the injection site of insulin rotated

to avoid lipodystrophy

what are the different sites of the body for insulin injection 

• abdomen

• thighs 

• upper arms

• buttocks 

what are the potential side effects of insulin use

• immune response- bovine —> porcine —> human - antibodies 

• local inflammaion at injection site 

• weight gain- dose related

• hypoglycaemia 

what are the goals of dietary management

• BMI 20-25

• blood glucose levels at normal range

• prevention of complications

• reduced lipid levels 

• improvement of overall health 

drugs for type 2 diabetes 

• biguanides- metformin

• sulfonylureas- increases secretion of insulin

• meglitinides- increases secretion of insulin

• glucosidase inhibitor- reduces rate of carbohydrate digestion

• PPARgamma agonsits- increases sensitivity to insulin

• GLP-1 and GIP agonists- inhibit glucagon release, stimulate insulin secretion

• DPP-4 inhibitors- decease glucagon levels

• SGLT- 2 inhibitors- inhibits glucose reuptake in kidney tissue lower serum glucose levels 

metformin

• does not involve insulin secretion

• reduces gluconeogensis in liver

• increases peripheral uptake of glucose and utilisation in skeletal msucle 

• increases sensitivity to insulin

• acts via AMPK, inhibits mitochondrial respiratory chain complex I —> increases GLP-1

PPAR gamma agonists

• pioglitazone

• bind to PPAR gamma—> regulation of genes involved in fatty acid storage and glucose metabolism 

• enhance activity of endogenous incretins 

• others in class no longer used due to increased risk of MI and liver damage 

sulphonylureas

• gliclazide

• block KATP channels in beta-cells; membrane depolarisation, Ca2+ entry, insulin release

• can cause hypoglycaemia 

• share sae mechanism as meglinitides 

DDP-4 inhibitors 

• algoliptin

• inhibit dipeptidyl peptidase- 4

• increase the half life go endogenous incretins (GLP-1)

• increases glucose-dependent insulin secretion

GLP-1 agonists

• semaglutide, ligraglutidde

• peptide mimics of human GLP-1 (modified to increase half-life and stability)

• bind to GLP-1 receptors —> regulation of genes involved in fatty acid storage and glucose metabolism 

• increase glucose- dependent insulin secretion, delay gastric emptying and inhibit glucagon secretion

SGLT-2 inhibitors

• dapagliflozin

• sodium glucose co-transporter mediates reabsorption of glucose in the kidney

• SGLT-2 inhibitors prevent reabsorption of glucose= increases exertion go glucose in urine

• increasesed excretion lowers blood glucose concs.

alpha-glucosidase inhibitors

• acarbose

• alpha-glucosidase breaks down short-chain oligosaccharides to glucose prior to glucose being absorbed in the GIT

• inhibitor of alpha-glucosidase reduces post-predial glucose absorption

• decrease in glucose absorption= decrease in blood glucose concs.

what does the body to to prevent diabetic ketoacidosis 

1. without insulin, glucose is unable to be processed by body 

2. the liver produces more glucose to feed the body, but without insulin, the glucose accumulates in the blood stream 

3. the body needs to find an alternative source of energy and starts breaking down fats. the breakdown of fat produces ketones, which then build up in the bloodstream 

4. ketones and glucose are transferred into the urine. the kidneys use water to clear the blood from excess glucose and ketones 

5. while the body attempts to get ride of ketones and glucose, a lot of water is lost. this can lead to dehydration and may worsen ketoacidosis 

what is the number of amino acids in the glucagon chain

• 31 amino acids

what type of hormone is glucagon

peptide hormone

how does glucagon act

• acts by stimulation of a cell surface GPCR

what does glucagon increase

• increases cAMP

• G alpha s 

when is glucagon secreted

• during times of fasting (between meals)

• from alpha-cells of the islets of langerhans

• decreased glucose

• increased secretion