No 46 - Diabetes: A deep dive into the history of diagnosis and treatment

This article will not be for everyone, but I found it interesting.

This week I have seen lots and lots of T2DM in primary care, diagnosed a few people with T2DM, seen an interesting onset of T1DM and possibly a diabetes insipidous.

I am also studying for the MRCGP AKT exam this year and thought this was a good prompt to read around the subject. Now, if you brain is like mine then it doesnt work like a filofax or a database. I can’t just recall lists of facts.

I have to find a way to “link” facts together so that I can either remember how things work or remember a story to tie it all together. Which is why I like to know the history of things, because if I can remember the story then it helps me remember the facts.

This post is going to be a deep dive into diabetes and is related to a few recent other posts:

No 45 - AKT Summary for T2DM QOF

No 37 - My plan for learning the history of modern medications

Ready? Here we go, everything you could ever want to know about diabetes (if you aren’t going to be a specialist):

[References are at the end]

1. When was the condition described and by who?

   1. Since 1552 BC – polyuria and polydipsia and weight loss

   2. Egyptian physician = Hesy-Ra,

   3. 230 BC = Apollonius of Memphis coined “diabetes” meaning a siphon

   4. 1675 Thomas Willis add mellitus meaning sweet (sweet tasting urine)

   5. 1936 = Harold Percival Himsworth differentiated T1DM and T2DM

2. What is the natural course?

   1. Classically diagnosed in children and adolescents, with the classic trio of symptoms

   2. 2 peaks for T1DM – Ages 5-7yo and near puberty

   3. Acidosis, coma and death

   4. T2DM – increased weight gain, increased risk of infections, cardiovascular disease, peripheral vascular disease, retinal issues and cancer. All leading to a reduced life expectancy and reduced QOL if not well managed.  

3. What is the prevalence?

   1. <20 years old in the US with T1DM and T2DM = 0.26% of the population (2.6/1000)

   2. <10 year old in the US with T1DM = 19.7/100,000

   3. >10yo with T1DM = 18.6/100,000

   4. Incidence increases further away from the equator. 0.1/100,000 in China, India and Venezuela, but 60/100,000 in Finland.

   5. T1DM = 20/100,000 in the UK

   6. 6.8% of the population of England has T2DM

   7. 463 million people globally have T1DM or T2DM and half of these are insulin dependent

4. What are the signs and symptoms?

   1. Polyuria, polyphagia, polydipsia, weight loss, pear-drop breath, coma,

5. What is the natural mortality and morbidity rate?

   1. Prior to the development of insulin or diet therapy, a child who developed T1DM might live for only 3 months.

   2. Following the starvation diet that might live for months to a few years.

   3. Leonard Thompson’s life (the first person to be treated with insulin) was extended 13 years. He had several episodes of ketoacidosis and hypoglycemia. He was hospitalized for ketoacidosis and died as an inpatient at TGH. His autopsy showed that he died of bronchopneumonia with some longer term complications of DM.

6. Are you likely to die from this or something else?

   1. T1DM was and is likely to significantly shorten your life expectancy, if not well managed.

   2. In the 1970s, T1DM was estimated to shorten life by 27 years.

   3. In the UK, Diabetes UK reports that T2DM will reduce life expectancy by 10 years and T1DM by 20 years.  

   4. In 2013, the European Association for the Study of Diabetes 2013 reported that the life expectancy of people with type 1 diabetes (aged 20–24 years) is about 11–14 years less.

   5. A recent paper suggests that T1DM on average will reduce life expectancy by 4 years and T2DM might not shorten life drastically in Bulgaria.

7. What was the first treatment and was it effective?

   1. 1776 – “Experiments and Observations on the Urine in Diabetics” by Matthew Dobson who was the first to discover sugar in the urine

   2. 1797 – John Rollo suggested a Nitrogenous diet (meat) for diabetes “Notes of a Diabetic Case”

   3. 1889 - Joseph von Mering and Oskar Minkowski removed the pancreas from dogs and realised they developed diabetes and died shortly afterward.

   4. 1910 - Sir Edward Albert Sharpey-Schafer proposed the idea of insulin

   5. 1913 - Frederick M. Allen developed a “diabetic diet” or “starvation diet” or “Eskimo diet” – very low calorie, high protein and fat. Calorie’s were severely restricted which prolonged life.

      1. The theory was a severely restricted diet and exercise would prolong the life of insulin-producing beta cells.

   6. 1960 – Fred Sanger determines the amino acid sequence of insulin enabling better manufacturing and then recombinant technology became available in the 1970s.

   7. 1980 – The Dietary Guidelines for Americans was first published and the Allen’s diet went out of favour. These guidelines recommended a low fat diet for “heart health”.

   8. 1921 - Fredrick Banting and Charles Best invented porcine insulin

8. When was the first trial? And by whom?

   1. 1921 - Fredrick Banting and Charles Best invented porcine insulin

9. When was the first guideline?

   1. 1926 – UK Medical Research Council guidance on insulin treatment

10. What is the current management?

·        Moran G M, Bakhai C, Song S H, Agwu J C. Type 2 diabetes: summary of updated NICE guidance BMJ 2022; 377 :o775 doi:10.1136/bmj.o775

·        https://cks.nice.org.uk/topics/diabetes-type-2/

·        Birmingham CCG T2DM Guideline

·        1921 - Insulin

·        1940 - Sulfonylureas (5)

·        1957 – Metformin

·        1970 – continuous subcutaneous infusion devices

·        SGLT-2 inhibitors (4)

·        DPP-4 inhibitors (5)

·        Pioglitazone (1)

·        GLP-1 receptor agonists (5)

1. What is the risk reduction?

   1. Well managed hyperglycaemia in T1DM and T2DM can almost prevent the complications of the diseases.

2. What is the NNT for each medication?

   1. (UKPDS) NNT for 10 years of treatment to prevent 1 MI or stroke =

      1. Metformin NNT = 14

      2. Sulfonylurea-insulin NNT = 29

   2. (UKPDS) NNT for 10 years treatment to prevent 1 death =

      1. Metformin NNT = 14

      2. Sulfonylurea-insulin NNT = 29

   3. Tight glycaemic control = no benefit at reducing stroke but 1/13 were harmed with hypoglycaemia. https://www.thennt.com/nnt/effect-tight-glycemic-control-patients-ischemic-stroke/ and https://www.thennt.com/nnt/insulin-for-glucose-control-in-ischemic-stroke/

      1. All of the above medications were searched on theNNT.com and google and NNT data was difficult to find.

   4. GLP-1a Liraglutide for 4 years to prevent 1 non fatal CV event = NNT = 55 https://academic.oup.com/eurheartj/article/39/24/2274/4604820  

   5. Empagliflozin for 3 years = NNT = 61 to prevent 1 non-fatal CV event  https://academic.oup.com/eurheartj/article/39/24/2274/4604820

   6. Adding Pioglitazone to other treatments for 3 years avoided 1 major CV event = NNT = 48  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291341/#:~:text=Adding%20pioglitazone%20to%20the%20medication,one%20first%20major%20CV%20event.

   7. Acarbose for 3 years to prevent 1 non-fatal CV event = NNT = 62  https://academic.oup.com/eurheartj/article/39/24/2274/4604820

   8. HbA1c reduced by 1-2% by Metformin or Sulfonylureas.

   9. HbA1c is reduced by 1-1.5% by Pioglitazone and Repaglinide.

   10. HbA1c reduced by 1% - GLP1 agonists and DPP4-inhibitors.

   11. HbA1c reduced by <1% - Acarbose and Pramlintide and Bromocriptine and Colesevelam and SGLT-2 inhibitors.

3. When was each medication discovered and by whom?

   1. 1922 – Banting and Best work with Eli Lilly to produce the first commercial insulin. This was rapid acting insulin. 1926 – insulin crystallization is developed and this allows for the production of longer acting insulins. 1936 – protamine zinc insulin is produced commercially and allows for fewer injections each day. 1946 – Nordisk produced their first long acting insulin. 1983 – recombinant human insulin made available instead of beef or pork insulin.

   2. 1937 - sulfonamide (Carbutamide and Tolbutamide- both in the sulfonylurea class of oral diabetes medications. Ruiz first noted synthetic sulfur compounds had hypoglycaemic effects. Janbon in 1942 confirmed this. 1956 – Tolbutamide was the first commercially produced sulfonylurea introduced in Germany.

      1. 1946 – Lobatieres discovered there sulfonylureas stimulate pancreatic B-cells to release insulin. 3rd generation drugs are now commonly used.

      2. The early work was conducted by Bayer AG and Boehringer Mannheim in Germany and Eli Lilly in the USA.

   3. 1957 - biguanide derivatives (Metformin) – Jean Sterne. Guanidine is found in Galega officinalis (goat’s rue or French lilac), the seeds and flowers had been used to treat polyuria since medieval times. First proven to reduce blood glucose in 1918. Other derivatives were used initially but had serious side effects and lactic acidosis. Introduced to the USA with FDA approval in 1994.

      1. Metformin is not metabolised but secreted by the kidney. It requires active transport out of the GI tract into the blood and active transport across the renal system into the urine. It had a high plasma concentration and is mostly concentrated in the liver and muscle. The therapeutic mechanism is not well understood, possibly alters mitochondrial and lysosomal function.

      2. Reduces glucose, therefore reduces insulin and IGF-1. This reduction may reduce the growth tumours. Obese patients with hyperglycaemia not on metformin are at increased risk of breast, prostate and colon cancer, also pancreatic and liver cancer.

   4. 1970 – first blood glucose monitor developed

   5. 1995 – Acarbose (a-Glucosidase inhibitors) – inhibits carbohydrate breakdown in the small intestines.

   6. 1997 – Repaglinide (Meglitinide). Insulin secretagogues. Short half life and reduces post-prandial insulin rise.

   7. 1999 – Pioglitazone (a Thiazolidinedione). Takeda Pharmaceuticals, Japan, make synthetic fibrates in the 1980s.

      1. They improve insulin sensitivity by binding to peroxisome proliferator activator receptors. They increase skeletal muscle insulin sensitivity and reduce hepatic glucose production. However, most of these drugs have been withdrawn from use due to liver damage or increased IHD or bladder cancer. It also causes oedema which can affect heart failure, and anaemic and osteoporosis. They do not cause hypoglycaemia.

   8. 2005 – Exanatide (GLP-1 agonist) was isolated from the saliva of the Gila monster. Twice daily injections before meals. A daily injection of Liraglutide was approved in 2010 and a weekly formulation was released in 2012.

      1. GLP-1 agonists cause GI SE, pancreatitis and possibly medullary thyroid cancers.

9.      2006 - GLP-1 is broken down by dipeptidyl peptidase-4 (DPP-4) in 2 minutes. sitagliptin, saxagliptin, and linagliptin are DPP4 inhibitors. They do not cause hypoglycaemia but can cause pancreatitis. They are weight neutral.

1. 2005 – Pramlintide is a synthetic amylin analog. It is secreted by B-cells with insulin and reduces post-prandial glucagon, hepatic glucogenesis, delays gastric emptying and induces weight loss.

2. 2008 – Colesevelam is a bile acid sequestrant that reduces LDL and glucose. Mechanism is not well understood.

3. 2009 – Bromocriptine was discovered to lower post-prandial glucose levels. It is a synthetic D2-agonist and its mechanism is not understood.

4. 2013 – SGLT-2 inhibitors (Canagliflozin, Dapagliflozin, Empagliflozin). The sodium glucose co-transporter 2 is in the kidneys and reabsorbs 90% of glucose from the urine. By inhibiting this transporter less glucose is reabsorbed from urine and more is excreted. They can help with weight loss but increase UTIs.

5. What are the main benefits of these treatments?

   1. Metformin – oral, weight loss (GDF15 secretion), lowers blood glucose but does NOT cause hypoglycaemia, increased insulin sensitivity, reduce hepatic gluconeogenesis, increase glucose uptake into muscles, long term cardiovascular benefits, reduction in LDL, ? anti-cancer, ? prolongs life, reduces nephropathy, improves PCOS, increases GLP1 secretion, changes gut flora, increases cytotoxic T-cells and CD8+ T cells.

   2. Glucagon-lie peptide 1 (GLP1) = incretin hormone secreted by enteroendocrine L cells. Promotes insulin secretion, inhibits glucagon release, slows gastric emptying, reduces appetite and food intake, no hypos, renal protection.  Weight loss.

   3. Sulfonylurea – lowers glucose, UKDPS study suggests a reduction in cardiovascular morbidity and mortality – although conflicting findings, limited benefit for microvascular protection.

   4. SGLT-2 inhibitors – lower glucose and weight loss, no hypos, cardio-protection and renal protection.  

   5. DPP4 inhibitors – lowers glucose, no hypos, no cardio-protection. Some renal protection.

   6. Pioglitazone (Thiazolidinedione, TZD) – lowers glucose, conflicting evidence about CVD protection or possibly increased risk.

   7. Repaglinide (Meglitinide) – lowers glucose  

   8. Pramlintide – lowers glucose, weight loss and feel fuller

   9. Colesevelam – lower glucose and LDL

   10. Acarbose (a-Glucosidase inhibitors) – lowers glucose absorption, weight loss,  

6. What are the major studies in this field?

   1. 1929 - Slotta and Tschesche – metformin animal models, hypoglycemic

   2. 1957 – Sterne – human trials

   3. 1998 - UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet. 1998;352:837–853. doi: 10.1016/S0140-6736(98)07019-6.

   4. 2005 – Evans J.M.M., Donnelly L.A., Emslie-Smith A.M., Alessi D.R., Morris A.D. Metformin and Reduced Risk of Cancer in Diabetic Patients. BMJ. 2005;330:1304–1305. doi: 10.1136/bmj.38415.708634.F7

   5. 2008 – (UKPDS) Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–1589. doi: 10.1056/NEJMoa0806470.

   6. 2008 – (ACCORD) The Action to Control Cardiovascular Risk in Diabetes Study Group Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–2559. doi: 10.1056/NEJMoa0802743.

   7. 2008 - The ADVANCE Collaborative Group Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–2572. doi: 10.1056/NEJMoa0802987.

   8. 2009 - Duckworth W, Abraira C, VADT Investigators et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–139. doi: 10.1056/NEJMoa0808431.

   9. 2010 - Yudkin JS, Richter B, Gale EA. Intensified glucose lowering in type 2 diabetes: time for a reappraisal. Diabetologia. 2010;53:2079–2085. doi: 10.1007/s00125-010-1864-z.

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